JP2015516000A - Bicyclic substituted uracils and uses thereof - Google Patents

Abstract

The present application relates to novel bicyclic substituted uracil derivatives, methods for their preparation, and methods for their use alone or in combination for the treatment and / or prevention of diseases, and for the treatment and / or prevention of diseases. It relates to the use of it for the manufacture of a medicament.

Description

  The present application relates to a novel bicyclic substituted uracil derivative, a process for its production, use alone or in combination for the treatment and / or prevention of diseases, and a medicament for the treatment and / or prevention of diseases. Relates to its use in manufacturing.

  Chymase is a chymotrypsin-like serine protease that is conserved as a macromolecular complex with heparin proteoglycans in the secretory vesicles of mast cells. When mast cells are activated, chymase is released into the extracellular matrix and activated.

  Activated mast cells play an important role in wound healing and inflammatory processes such as wound fibrosis, angiogenesis and cardiac remodeling (Miyazaki et al., Pharmacol. Ther. 112 (2006), 668-676). Shiota et al., J. Hypertens. 21 (2003), 1823-1825). In the case of heart failure, myocardial infarction and ischemia, an increase in the number of mast cells has been observed in human atherosclerotic plaques and abdominal aortic aneurysms (Kovanen et al., Circulation 92 (1995), 1084-1088; Libby and Shi, Circulation). 115 (2007), 2555-2558; Bacani and Frisman, Cardiol. Rev. 14 (4) (2006), 187-193). Chymase positive mast cells may also play an important role in airway vascular remodeling in the case of asthma and chronic obstructive pulmonary disease. An increase in the number of mast cells has been observed in endobronchial biopsies of asthmatic patients (Zanini et al., J. Allergy Clin. Immunol. 120 (2007), 329-333). In addition, chymase is suspected to be partly involved in the development of many kidney disorders such as diabetic nephropathy and polycystic kidney disease (Huang et al., J. Am. Soc. Nephrol. 14 (7 ) (2003), 1738-1747; McPherson et al., J. Am. Soc. Nephrol. 15 (2) (2004), 493-500).

  Chymase is primarily involved in the production of angiotensin II in the heart, arterial wall and lung, while angiotensin converting enzyme is involved in the formation of its peptide in the circulatory system (Fleming I., Circ. Res. 98 (2006), 887-896). ). In addition, chymase cleaves many other pathologically important substrates. Chymase degrades extracellular matrix proteins such as fibronectin, procollagen and vitronectin and stops focal adhesions. This results in activation and release from the latent form of TGFβ, which plays an important role in the development of cardiac hypertrophy and cardiac fibrosis. The enzyme has an atherogenic action by degrading apolipoprotein and preventing absorption of cholesterol by HDL. The action of chymase results in the release and activation of the cytokine pro-inflammatory cytokine interleukin-1. Furthermore, it contributes to the production of endothelin 1 (Bacani and Frisman, Cardiol. Rev. 14 (4) (2006), 187-193). Biopsy of patients with atopic dermatitis, Crohn's disease, chronic hepatitis and cirrhosis, and idiopathic interstitial pneumonia has shown accumulation of chymase positive mast cells (Dogrel S. A., Expert Opin. Ther. Patents). 18 (2008), 485-499).

Miyazaki et al. Pharmacol. Ther. 112 (2006), 668-676 Shiota et al. , J. et al. Hypertens. 21 (2003), 1823-1825 Kovanen et al. , Circulation 92 (1995), 1084-1088. Libby and Shi, Circulation 115 (2007), 2555-2558 Bacani and Frisman, Cardiol. Rev. 14 (4) (2006), 187-193 Zanini et al. , J. et al. Allergy Clin. Immunol. 120 (2007), 329-333 Huang et al. , J. et al. Am. Soc. Nephrol. 14 (7) (2003), 1738-1747 McPherson et al. , J. et al. Am. Soc. Nephrol. 15 (2) (2004), 493-500 Fleming I. , Circ. Res. 98 (2006), 887-896 Bacani and Frisman, Cardiol. Rev. 14 (4) (2006), 187-193 Dogrel S.M. A. , Expert Opin. Ther. Patents 18 (2008), 485-499.

  The possibility of using chymase inhibitors in the treatment of various diseases has been shown in many studies involving animal experiments. Chymase inhibition can be useful in the treatment of myocardial infarction. Jin et al. (Pharmacol. Exp. Ther. 309 (2004), 409-417) found that ligating the coronary arteries in dogs caused ventricular arrhythmias, resulting in increased angiotensin II production and increased chymase activity in the heart. Revealed. Intravenous administration of the chymase inhibitor TY-501076 decreased chymase activity, decreased the angiotensin II concentration in plasma, and suppressed the occurrence of arrhythmia. In vivo models of myocardial infarction in hamsters show favorable effects of chymase inhibition. Treating animals with the chymase inhibitor BCEAB reduced chymase activity, improved hemodynamics, and reduced mortality (Jin et al., Life Sci. 71 (2002), 437-446). In Syrian hamsters with cardiomyopathy with high numbers of mast cells in the heart, oral administration of chymase inhibitors to animals reduced cardiac fibrosis by 50% (Takai et al., Jpn. J. Pharmacol. 86 (2001). ), 124-126). In tachycardia-induced heart failure in dogs, inhibition of chymase by SUN-C82257 reduced the number of mast cells and reduced fibrosis in the heart. In addition, cardiac diastolic function improved after treatment (Matsumoto et al., Circulation 107 (2003), 2555-2558).

  Chymase inhibition therefore constitutes an effective principle in the treatment of cardiovascular disorders, inflammation and allergic disorders, and various fibrotic disorders.

  WO2007 / 150011 and WO2009 / 049112 disclose methods for producing pyrimidinetriones having a glycine substituent. WO 2008/056257 describes triazinediones as GABA-B receptor modulators for the treatment of CNS disorders. WO 2008/103277 discloses various nitrogen-based heterocycles for cancer treatment. WO2009 / 156182 describes uracil derivatives for suppressing or reducing the expression of resistance during cell growth inhibition therapy. The object of the present invention was to provide novel substances which act as inhibitors of chymase and which are suitable per se in the treatment and / or prevention of disorders, in particular cardiovascular disorders.

The present invention relates to compounds of general formula (I) and salts, solvates and solvates of the salts thereof.

Where
R ¹ is hydrogen or (C ₁ -C ₄ ) -alkyl;
R ² is a group of the following formula:

And
Where
^* Is the bonding site to the uracil nitrogen atom,
A is —CH ₂ — or oxygen,
m is the number 0, 1 or 2;
R ⁴ is halogen, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, difluoromethoxy, trifluoromethoxy or (C ₁ -C ₄ ) -alkoxy;
R ^5A is hydrogen or deuterium;
R ^5B is hydrogen, deuterium or (C ₁ -C ₄ ) -alkyl;
R ⁶ is hydrogen or fluorine;
R ⁷ is hydrogen or fluorine,
R ⁸ is halogen, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl or nitro;
R ⁹ is hydrogen, halogen, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, nitro or (C ₁ -C ₄ ) -alkylthio;
R ³ is a group of the following formula:

And
Where
# Is the point of attachment to the uracil nitrogen atom,
Ring Q is a 5- to 7-membered heterocycle or 5- or 6-membered heteroaryl, wherein
5- to 7-membered heterocycle and 5- or 6-membered heteroaryl are halogen, difluoromethyl, trifluoromethyl, trideuterated methyl, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) — Independently selected from the group of cycloalkyl, oxo, hydroxyl, (C ₁ -C ₄ ) -alkylcarbonyl, (C ₁ -C ₄ ) -alkoxycarbonyl, aminocarbonyl and (C ₁ -C ₄ ) -alkylsulfonyl Optionally substituted by 1 to 4 substituents,
(C ₁ -C ₆ ) -alkyl and (C ₃ -C ₇ ) -cycloalkyl are then halogen, cyano, trifluoromethyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl, (C ₁ -C ₄ ) -Alkoxy and optionally substituted by 1 to 3 substituents independently selected from the group of 4 to 7 membered heterocycles;
Two (C ₁ -C ₆ ) -alkyl groups attached to a 5- to 7-membered heterocycle and a 5- or 6-membered heteroaryl carbon atom together with the carbon atom to which they are attached It may form a 6-membered carbocycle,
R ²⁴ is halogen, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -alkoxy,
n is the number 0, 1, 2, or 3.

The present invention relates to compounds of the following general formula (I) and salts, solvates and solvates of the salts thereof.

Where
R ¹ is hydrogen or (C ₁ -C ₄ ) -alkyl;
R ² is a group of the following formula:

And
Where
^* Is the bonding site to the uracil nitrogen atom,
A _{is, -CH 2 -, - CH 2} -CH 2 -, - O-CH 2 - is ## or oxygen,
## is the bonding point to the phenyl ring,
m is the number 0, 1 or 2;
R ⁴ is halogen, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, difluoromethoxy, trifluoromethoxy or (C ₁ -C ₄ ) -alkoxy;
R ^5A is hydrogen or deuterium;
R ^5B is hydrogen, deuterium or (C ₁ -C ₄ ) -alkyl;
R ⁶ is hydrogen or fluorine;
R ⁷ is hydrogen or fluorine,
R ⁸ is halogen, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl or nitro;
R ⁹ is hydrogen, halogen, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, nitro or (C ₁ -C ₄ ) -alkylthio;
R ³ is a group of the following formula:

And
Where
# Is the point of attachment to the uracil nitrogen atom,
Ring Q is a 5- to 7-membered heterocycle or 5- or 6-membered heteroaryl, wherein 5- to 7-membered heterocycle and 5- or 6-membered heteroaryl are halogen, difluoromethyl, trifluoromethyl, tri deuterated _{methyl, (C} 1 -C ₆₎ - _{alkyl, (C} 3 -C ₇₎ - cycloalkyl, oxo, _{hydroxyl, (C} 1 -C ₄₎ - _{alkylcarbonyl,} (C 1 _-C 4) - Optionally substituted by 1 to 4 substituents independently selected from the group of alkoxycarbonyl, aminocarbonyl and (C ₁ -C ₄ ) -alkylsulfonyl,
(C ₁ -C ₆ ) -alkyl and (C ₃ -C ₇ ) -cycloalkyl are then halogen, cyano, trifluoromethyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl, (C ₁ -C ₄ ) -Alkoxy and optionally substituted by 1 to 3 substituents independently selected from the group of 4 to 7 membered heterocycles;
Two (C ₁ -C ₆ ) -alkyl groups attached to a 5- to 7-membered heterocycle and a 5- or 6-membered heteroaryl carbon atom together with the carbon atom to which they are attached It may form a 6-membered carbocycle,
R ²⁴ is halogen, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -alkoxy,
n is the number 0, 1, 2, or 3.

  The compounds of the invention are encompassed by the formula (I) and the compounds described below and the salts thereof, as long as the compounds described below are not yet salts, solvates and solvates of the salts. , Solvates and solvates of salts, compounds encompassed by formula (I) of the formulas described below and salts, solvates and solvates of salts thereof, and by formula (I) And the compounds described below as working examples and salts, solvates and solvates of the salts thereof.

  In the context of the present invention, preferred salts are physiologically acceptable salts of the compounds of the invention. Also included are salts that are not themselves suitable for pharmaceutical use, but can be used, for example, for the isolation, purification or storage of the compounds of the invention.

  Physiologically acceptable salts of the compounds of the present invention include addition salts of mineral acids, carboxylic acids and sulfonic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid. , Toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

  Physiologically acceptable salts of the compounds of the present invention include conventional base salts such as preferably alkali metal salts (eg, sodium and potassium salts), alkaline earth metal salts (eg, calcium). And magnesium salts) and ammonia or organic amines having 1 to 16 carbon atoms, such as preferably ethylamine, diethylamine, triethylamine, N, N-ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol, Ammonium salts derived from diethylaminoethanol, procaine, dicyclohexylamine, dibenzylamine, N-methylpiperidine, N-methylmorpholine, arginine, lysine, choline and 1,2-ethylenediamine A.

  In the context of the present invention, a solvate refers to a form of a compound of the present invention that is solid or liquid and forms a complex by coordination of solvent molecules. Hydrates are a specific form of solvates whose coordination is due to water. Preferred solvates in the context of the present invention are hydrates.

  Depending on the structure, the compounds of the invention can exist in different stereoisomeric forms, ie in the form of configurational isomers or, where appropriate, as conformational isomers (enantiomers and And / or diastereomers, as in the case of atropisomers). The invention therefore encompasses the enantiomers or diastereomers and their individual mixtures. Stereoisomerically homogeneous components can be isolated from such mixtures of enantiomers and / or diastereomers in a known manner. Chromatographic processes are preferably used for this, in particular HPLC chromatography in achiral or chiral phases.

  Where the compounds of the invention can be tautomeric, the invention encompasses all tautomeric forms.

The present invention also includes all suitable isotopic forms of the compounds of the invention. Isotopic forms of the compounds of the invention are those herein wherein at least one atom in the compound of the invention has the same atomic number, but has an atomic mass different from that which is normal or predominant in nature. Is understood to mean a compound that has been exchanged for Examples of isotopes that can be incorporated into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium), ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I ¹²⁴ I, ¹²⁹ I and ¹³¹ I. Certain isotopic forms of the compounds of the invention, particularly those incorporating one or more radioactive isotopes, may be useful, for example, for testing the mechanism of action or active ingredient distribution in the body. In particular, compounds labeled with ³ H or ¹⁴ C isotopes are suitable for this purpose because of their relative ease of production and detection. In addition, the incorporation of isotopes such as deuterium increases the metabolic stability of the compound, for example, increasing the half-life in the body and reducing the required active ingredient dose, making it particularly beneficial for treatment. obtain. Accordingly, such modifications of the compounds of the present invention can optionally constitute preferred embodiments of the present invention. Isotopic forms of the compounds of the invention can be obtained by corresponding isotopic modifications of a particular reagent and / or starting compound therein by methods known to those skilled in the art, for example, by instructions reproduced in the methods and working examples described below. It can be manufactured by using.

  The invention further encompasses prodrugs of the compounds of the invention. The term “prodrug” as used herein is either biologically active or biologically inactive, but is converted to a compound of the present invention while present in the body, eg, by metabolic or hydrolysis pathways. Is a compound.

  In the context of this invention, unless otherwise indicated, each substituent is defined as follows:

  In the context of the present invention, “alkyl” is a linear or branched alkyl group having the specified number of carbon atoms in each case. Preferred examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3 -Methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,4-dimethylpentyl, 4 1,4-dimethylpentyl and 1,4,4-trimethylpentyl.

  In the context of the present invention, “cycloalkyl” is a monocyclic saturated alkyl group having 3 to 7 carbon atoms. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

  In the context of the present invention, “alkylcarbonyl” is a straight-chain or branched alkyl group having 1 to 4 carbon atoms and a carbonyl group bonded in position 1. Preferred examples include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl and tert-butylcarbonyl.

  In the context of the present invention, “alkoxy” is a straight-chain or branched alkoxy group having 1 to 4 carbon atoms. Preferred examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

  In the context of the present invention, “alkoxycarbonyl” is a straight or branched alkoxy group having a carbonyl group bonded to 1 to 4 carbon atoms and oxygen. Preferred examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

  In the context of the present invention, “alkylthio” is a straight-chain or branched alkyl group having 1 to 4 carbon atoms and bonded via a sulfur atom. Preferred examples include methylthio, ethylthio, n-propylthio, isopropylthio, 1-methylpropylthio, n-butylthio, iso-butylthio and tert-butylthio.

  In the context of this invention an “alkylsulfonyl” is a straight or branched alkyl group having 1 to 4 carbon atoms and attached via a sulfonyl group. Preferred examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl and tert-butylsulfonyl.

In the context of the present invention, "4 to 7 membered heterocyclic ring" includes a 4 to 7 ring atoms in total, N, O, S, 1 or 2 from the group of SO and / or SO ₂ A monocyclic saturated heterocycle containing 1 ring heteroatom and attached via a ring carbon atom or, where appropriate, a ring nitrogen atom. Examples include azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and the like. Preference is given to azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl and morpholinyl.

In the context of the present invention, a “5- to 7-membered heterocycle” has a total of 5 to 7 ring atoms and is 1 to 3 ring heteroatoms from the group of N, O, S and / or SO ₂ And a partially unsaturated heterocyclic ring fused to the phenyl ring at R ³ . Examples include dihydropyrrolyl, dihydroimidazolyl, dihydrothiazole dioxide, dihydrooxazolyl, dihydropyridyl, tetrahydropyrazinyl and dihydrooxazinyl.

In the context of the present invention, “heteroaryl” has a total of 5 or 6 ring atoms and contains no more than 3 identical or different ring heteroatoms from the group N, O and / or S, and R ³ is a monocyclic aromatic heterocycle fused to a phenyl ring (heteroaromatic). Examples include furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl. Preference is given to pyrazolyl, imidazolyl, thiazolyl and triazolyl.

  In the context of the present invention, “halogen” includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.

  In the context of the present invention, an “oxo group” is an oxygen atom bonded to a carbon or sulfur atom via a double bond.

In the formula of the group that R ² and R ³ can represent, the end of the line marked with the symbol ^* or # or ## does not represent a carbon atom or a CH ₂ group, but R ² and R ³ Is part of the bond to the individual atom to which is attached.

  When a group in a compound according to the present invention is substituted, the group can be mono- or poly-substituted unless otherwise noted. In the context of the present invention, all groups which are present a plurality of times are all defined independently of each other. Substitution with one or two identical or different substituents is preferred. Very particular preference is given to substitution with one substituent.

  In the context of the present invention, “treatment” or “treating” refers to inhibition of the development, course or progression of a disease, condition, disorder, trauma or health problem, or such condition and / or symptoms of such condition. , Delay, suppression, mitigation, attenuation, limitation, reduction, deterrence, combat or cure. The term “therapy” is understood herein to be synonymous with the term “treatment”.

  The terms “prevention”, “prevention” or “prevention” are used interchangeably in the context of the present invention and are at risk of suffering, experiencing, suffering from or having a disease, condition, disorder, trauma or health problem, or the like Refers to avoiding or reducing the development or progression of a condition and / or symptoms of such condition.

  Treatment or prevention of a disease, condition, disorder, trauma or health problem may be partial or complete.

Preferred in the context of the present invention is
R ¹ is hydrogen, methyl or ethyl;
R ² is a group of the following formula:

And
Where
^* Is the bonding site to the uracil nitrogen atom,
A is —CH ₂ — or oxygen,
R ^4A is hydrogen, fluorine, chlorine, trifluoromethyl or methyl;
R ^4B is hydrogen, fluorine, chlorine, trifluoromethyl or methyl;
Provided that at least one of the R ^4A and R ^4B groups is other than hydrogen;
R ^5A is hydrogen;
R ^5B is hydrogen;
R ⁶ is hydrogen;
R ⁷ is hydrogen;
R ⁸ is fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl;
R ⁹ is fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl;
R ³ is a group of the following formula:

And
Where
# Is the bonding site to the uracil nitrogen atom,
E ¹ is CR ¹¹ or N;
R ¹¹ is hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or aminocarbonyl;
E ² is CR ¹² or N;
R ¹² is hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl;
E ³ is NR ¹⁴ or S;
R ¹⁴ is hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl;
G ¹ is C═O or SO ₂ ,
G ² is CR ^16A R ^16B , NR ¹⁷ , O or S;
R ^16A is hydrogen, fluorine, (C ₁ -C ₄ ) -alkyl or hydroxyl;
R ^16B is hydrogen, fluorine, chlorine, (C ₁ -C ₄ ) -alkyl or trifluoromethyl;
Or R ^16A and R ^16B together with the carbon atom to which they are attached form a 3- to 6-membered carbocycle;
R ¹⁷ is hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or (C ₁ -C ₄ ) -alkoxycarbonyl;
(C ₁ -C ₆ ) -alkyl is fluorine, trifluoromethyl, cyano, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, azetidinyl, oxetanyl, Optionally substituted by 1 to 3 substituents independently selected from the group of tetrahydrofuranyl and pyrrolidinyl,
G ³ is CR ^18A R ^18B , NR ¹⁹ , O or S;
R ^18A is hydrogen, fluorine, (C ₁ -C ₄ ) -alkyl or hydroxyl;
R ^18B is hydrogen, fluorine, chlorine, (C ₁ -C ₄ ) -alkyl or trifluoromethyl;
Or R ^18A and R ^18B together with the carbon atom to which they are attached form a 3 to 6 membered carbocycle;
R ¹⁹ is hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or (C ₁ -C ₄ ) -alkoxycarbonyl;
(C ₁ -C ₆ ) -alkyl is fluorine, trifluoromethyl, cyano, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, azetidinyl, oxetanyl, Optionally substituted by 1 to 3 substituents independently selected from the group of tetrahydrofuranyl and pyrrolidinyl,
G ⁴ is CH ₂ , C═O or SO ₂ ,
K ¹ is CH ₂ or O;
K ² is CH ₂ or O;
Provided that only one of the K ¹ and K ² groups is O;
D ¹ , D ² , D ³ and D ⁴ are each independently CR ²³ or N;
R ²³ is hydrogen, halogen, (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,
Provided that no more than ^{two of} the D ¹ , D ² , D ³ and D ⁴ groups are N;
R ²⁴ is fluorine or methyl;
n is the number 0 or 1;
R ¹⁰ is (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl;
₁ or _{2 wherein} (C ₁ -C ₄ ) -alkyl is independently selected from the group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl May be substituted by a substituent,
R ¹³ is hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl;
R ¹⁵ is hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl;
₁ or 2 wherein (C ₁ -C ₆ ) -alkyl is independently selected from the group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl May be substituted by a substituent,
R ²⁰ is hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or (C ₁ -C ₄ ) -alkylcarbonyl;
₁ or 2 wherein (C ₁ -C ₆ ) -alkyl is independently selected from the group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl May be substituted by a substituent,
R ²¹ is hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or (C ₁ -C ₄ ) -alkylsulfonyl;
R ^22A is hydrogen or (C ₁ -C ₄ ) -alkyl;
R ^22B is hydrogen or (C ₁ -C ₄ ) -alkyl;
Or a compound of formula (I) wherein R ^22A and R ^22B form a carbonyl group with the carbon atom to which they are attached, and salts, solvates and solvates of the salts thereof.

In the context of the present invention, preferred are
R ¹ is hydrogen, methyl or ethyl;
R ² is a group of the following formula:

And
Where
^* Is the bonding site to the uracil nitrogen atom,
A is _{-CH 2 -, - CH 2 -CH} 2 -, - O-CH 2 - is ## or oxygen,
## is the bonding site to the phenyl ring,
R ^4A is hydrogen, fluorine, chlorine, trifluoromethyl or methyl;
R ^4B is hydrogen, fluorine, chlorine, trifluoromethyl or methyl;
Provided that at least one of the R ^4A and R ^4B groups is other than hydrogen;
R ^5A is hydrogen;
R ^5B is hydrogen;
R ⁶ is hydrogen;
R ⁷ is hydrogen;
R ⁸ is fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl;
R ⁹ is fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl;
R ³ is a group of the following formula:

And
Where
# Is the bonding site to the uracil nitrogen atom,
E ¹ is CR ¹¹ or N;
R ¹¹ is hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or aminocarbonyl;
E ² is CR ¹² or N;
R ¹² is hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl;
E ³ is NR ¹⁴ or S;
R ¹⁴ is hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl;
G ¹ is C═O or SO ₂ ,
G ² is CR ^16A R ^16B , NR ¹⁷ , O or S;
R ^16A is hydrogen, fluorine, (C ₁ -C ₄ ) -alkyl or hydroxyl;
R ^16B is hydrogen, fluorine, chlorine, (C ₁ -C ₄ ) -alkyl or trifluoromethyl;
Or R ^16A and R ^16B together with the carbon atom to which they are attached form a 3 to 6 membered carbocycle;
R ¹⁷ is hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or (C ₁ -C ₄ ) -alkoxycarbonyl;
(C ₁ -C ₆ ) -alkyl is fluorine, trifluoromethyl, cyano, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, azetidinyl, oxetanyl, Optionally substituted by 1 to 3 substituents independently selected from the group of tetrahydrofuranyl and pyrrolidinyl,
G ³ is CR ^18A R ^18B , NR ¹⁹ , O or S;
R ^18A is hydrogen, fluorine, (C ₁ -C ₄ ) -alkyl or hydroxyl;
R ^18B is hydrogen, fluorine, chlorine, (C ₁ -C ₄ ) -alkyl or trifluoromethyl;
Or R ^18A and R ^18B may form a 3- to 6-membered carbocycle with the carbon atom to which they are attached,
R ¹⁹ is hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or (C ₁ -C ₄ ) -alkoxycarbonyl;
(C ₁ -C ₆ ) -alkyl is fluorine, trifluoromethyl, cyano, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, azetidinyl, oxetanyl, Optionally substituted by 1 to 3 substituents independently selected from the group of tetrahydrofuranyl and pyrrolidinyl,
G ⁴ is CH ₂ , C═O or SO ₂ ,
K ¹ is CH ₂ or O;
K ² is CH ₂ or O;
Provided that only one of the K ¹ and K ² groups is O;
D ¹ , D ² , D ³ and D ⁴ are each independently CR ²³ or N, R ²³ is hydrogen, halogen, (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl ,
Provided that no more than ^{two of} the D ¹ , D ² , D ³ and D ⁴ groups are N;
R ²⁴ is fluorine or methyl;
n is the number 0 or 1;
R ¹⁰ is (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl;
₁ or _{2 wherein} (C ₁ -C ₄ ) -alkyl is independently selected from the group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl May be substituted by a substituent,
R ¹³ is hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl;
R ¹⁵ is hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl;
₁ or 2 wherein (C ₁ -C ₆ ) -alkyl is independently selected from the group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl May be substituted by a substituent,
R ²⁰ is hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or (C ₁ -C ₄ ) -alkylcarbonyl;
₁ or 2 wherein (C ₁ -C ₆ ) -alkyl is independently selected from the group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl May be substituted by a substituent,
R ²¹ is hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or (C ₁ -C ₄ ) -alkylsulfonyl;
R ^22A is hydrogen or (C ₁ -C ₄ ) -alkyl;
R ^22B is hydrogen or (C ₁ -C ₄ ) -alkyl;
Or a compound of formula (I) and salts, solvates and solvates of the salts thereof, wherein R ^22A and R ^22B form a carbonyl group with the carbon atom to which they are attached.

Particularly preferred in the context of the present invention are
R ¹ is hydrogen;
R ² is a group of the following formula:

And
Where
^* Is the bonding site to the uracil nitrogen atom,
A is —CH ₂ —;
R ^4A is chlorine or trifluoromethyl;
R ^4B is hydrogen;
R ³ is a group of the following formula:

And
Where
# Is the bonding site to the uracil nitrogen atom,
E ¹ is CR ¹¹
R ¹¹ is hydrogen;
E ² is N;
G ¹ is C = O,
G ² is CR ^16A R ^16B , NR ¹⁷ , O or S;
R ^16A is hydrogen, fluorine, methyl or hydroxyl;
R ^16B is hydrogen, fluorine, methyl or trifluoromethyl;
Or R ^16A and R ^16B together with the carbon atom to which they are attached form a cyclopropyl ring;
R ¹⁷ is hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₅ ) -cycloalkyl;
(C ₁ -C ₄ ) -alkyl is independently selected from the group of fluorine, trifluoromethyl, cyano, cyclopropyl, cyclobutyl, hydroxyl, trifluoromethoxy, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl. Optionally substituted by 1 to 3 substituents,
R ²⁴ is hydrogen or fluorine,
R ¹⁰ is (C ₁ -C ₄ ) -alkyl;
R ¹⁵ is hydrogen, methyl or ethyl;
Compounds of formula (I) in which methyl and ethyl may be substituted by one substituent selected from the group of fluorine, trifluoromethyl and cyclopropyl and salts, solvates and solvates of the salts thereof It is a thing.

Also preferred in the context of the present invention is
R ¹ is hydrogen;
R ² is a group of the following formula:

And
Where
^* Is the bonding site to the uracil nitrogen atom,
R ^5A is hydrogen;
R ^5B is hydrogen;
R ⁶ is hydrogen;
R ⁷ is hydrogen;
R ⁸ is fluorine, chlorine or trifluoromethyl;
R ⁹ is fluorine, chlorine, trifluoromethyl or methyl;
R ³ is a group of the following formula:

And
Where
# Is the bonding site to the uracil nitrogen atom,
E ¹ is CR ¹¹ and R ¹¹ is hydrogen;
E ² is N;
G ¹ is C = O,
G ² is CR ^16A R ^16B , NR ¹⁷ , O or S;
R ^16A is hydrogen, fluorine, methyl or hydroxyl;
R ^16B is hydrogen, fluorine, methyl or trifluoromethyl;
Or R ^16A and R ^16B together with the carbon atom to which they are attached form a cyclopropyl ring;
R ¹⁷ is hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₅ ) -cycloalkyl;
(C ₁ -C ₄ ) -alkyl is independently selected from the group of fluorine, trifluoromethyl, cyano, cyclopropyl, cyclobutyl, hydroxyl, trifluoromethoxy, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl. Optionally substituted by 1 to 3 substituents,
R ²⁴ is hydrogen or fluorine,
R ¹⁰ is (C ₁ -C ₄ ) -alkyl;
R ¹⁵ is hydrogen, methyl or ethyl;
Compounds of formula (I) in which methyl and ethyl may be substituted by one substituent selected from the group of fluorine, trifluoromethyl and cyclopropyl and salts, solvates and solvates of the salts thereof It is a thing.

Also preferred in the context of the present invention is
R ¹ is hydrogen, methyl or ethyl;
R ² is a group of the following formula:

And
Where
^* Is the bonding site to the uracil nitrogen atom,
A is —CH ₂ —;
R ^4A is chlorine or trifluoromethyl;
Compounds of formula (I) wherein R ^4B is hydrogen and salts, solvates and solvates of the salts thereof.

Also preferred in the context of the present invention is
R ³ is a group of the following formula:

And
Where
# Is the bonding site to the uracil nitrogen atom,
E ¹ is CR ¹¹ or N;
R ¹¹ is hydrogen, methyl, ethyl or aminocarbonyl;
E ² is CR ¹² or N;
R ¹² is hydrogen;
G ¹ is C═O or SO ₂ ,
G ² is CR ^16A R ^16B , NR ¹⁷ , O or S;
R ^16A is hydrogen, fluorine, methyl or hydroxyl;
R ^16B is hydrogen, fluorine, chlorine, methyl or trifluoromethyl;
Or R ^16A and R ^16B together with the carbon atom to which they are attached form a cyclopropyl ring;
R ¹⁷ is hydrogen, (C ₁ -C ₄ ) -alkyl, cyclopropyl or cyclobutyl;
(C ₁ -C ₄ ) -alkyl may be substituted by one or two substituents independently selected from the group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, azetidinyl and oxetanyl ,
G ³ is CR ^18A R ^18B and R ^18A is hydrogen, fluorine, methyl or hydroxyl,
R ^18B is hydrogen, fluorine, methyl or trifluoromethyl;
G ⁴ is C = O,
K ¹ is CH ₂ or O;
K ² is CH ₂
R ²⁴ is hydrogen, fluorine or methyl;
R ¹⁰ is methyl or ethyl;
R ¹⁵ is methyl or ethyl;
R ²⁰ is hydrogen, methyl, ethyl or methylcarbonyl;
R ²¹ is methyl or ethyl;
R ^22A and R ^22B are the compounds of formula (I) and the salts, solvates and solvates of the salts which form a carbonyl group with the carbon atom to which they are attached.

Also preferred in the context of the present invention is
R ² is a group of the following formula:

And
Where
^* Is the bonding site to the uracil nitrogen atom,
A is —CH ₂ —;
R ^4A is chlorine or trifluoromethyl;
R ^4B is hydrogen;
Compounds of formula (I) in which the carbon atom bound to the uracil nitrogen atom has the R configuration and salts, solvates and solvates of the salts thereof.

Also preferred in the context of the present invention is
R ² is a group of the following formula:

And
Where
^* Is the bonding site to the uracil nitrogen atom,
A is —CH ₂ —;
R ^4A is hydrogen, fluorine, chlorine, trifluoromethyl or methyl;
R ^4B is hydrogen, fluorine, chlorine, trifluoromethyl or methyl;
Provided that at least one of the R ^4A and R ^4B groups is other than hydrogen;
Compounds of formula (I) in which the carbon atom bound to the uracil nitrogen atom has the R configuration and salts, solvates and solvates of the salts thereof.

  Individual group definitions described in a particular combination or preferred combination of groups are also replaced by the group definitions of other combinations, as desired, independently of the particular combination of groups described.

  Very particularly preferred are combinations of two or more of the above preferred ranges.

The present invention further includes
[A] Compound of the following formula (II):

(Where
R ^1A is (C ₁ -C ₄ ) -alkyl;
T ¹ is (C ₁ -C ₄ ) -alkyl;
T ² is (C ₁ -C ₄ ) -alkyl. ) In an inert solvent, optionally in the presence of a suitable base:

(Wherein R ³ is as defined above) and a compound of the following formula (IV):

(Wherein R ^1A and R ³ are each as defined above)
This is then carried out in the presence of a suitable base in an inert solvent in the following formula (V):

(Where
R ² is as defined above,
X ¹ is hydroxyl or a suitable leaving group, in particular chlorine, bromine or iodine. And a compound of the following formula (I-1):

In which R ^1A , R ² and R ³ are each as defined above.
Or [B] a compound of formula (VI):

(Where
R ^1A and T ¹ are each as defined above,
T ³ is (C ₁ -C ₄ ) -alkyl. ) With a compound of formula (III) in an inert solvent or without solvent, a compound of formula (VII)

(Wherein R ^1A , R ³ and T ³ are each as defined above),
This is then reacted with chlorosulfonyl isocyanate in an inert solvent to give a compound of formula (IV), which is then converted to a compound of formula (I-1) in a manner similar to method [A]. ,
Or [C] a compound of the following formula (VIII):

(Wherein R ² is as defined above) in an inert solvent compound of formula (IX):

(Where
R ^1A and T ¹ are each as defined above, and T ⁵ is (C ₁ -C ₄ ) -alkyl. )
Cyclization in the presence of a suitable base gives a compound of formula (X)

(Wherein R ^1A and R ² are each as defined above) and are then obtained in the presence of a suitable catalyst and a suitable base in an inert solvent in the following formula (XI ) Compound:

(Where
R ³ is as defined above,
T ⁶ is hydrogen, (C ₁ -C ₄ ) -alkyl, or the two T ⁶ groups together form a —C (CH ₃ ) ₂ —C (CH ₃ ) ₂ — bridge. To obtain a compound of formula (I-1),
Or [D] hydrolyzing the compound of formula (I-1) in the presence of a suitable acid or base in an inert solvent to give a compound of formula (I-2):

(Where
R ² and R ³ are each as defined above,
R ^1B is hydrogen. )
The protecting group is removed and / or, where appropriate, and / or the compounds of formulas (I-1) and (I-2) are used with a suitable (i) solvent and / or (ii) a base or acid. A process for the preparation of a compound of formula (I) of the present invention, which is converted to a solvate, salt and / or salt solvate thereof.

  Together, the compounds of formula (I-1) and (I-2) form the group of compounds of formula (I) of the present invention.

  Inert solvents in process step (II) + (III) → (IV), (VI) + (III) → (VII) and (VIII) + (IX) → (X) are, for example, diethyl ether, dioxane, Ethers such as tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fraction, halohydrocarbons such as dichloromethane, 1,2-dichloroethane, trichloroethylene or chlorobenzene, methanol, ethanol , Alcohols such as n-propanol, isopropanol or n-butanol, or dimethylformamide, dimethyl sulfoxide, N, N′-dimethylpropyleneurea (DMPU), N-methyl Pyrrolidinone (NMP), pyridine, acetone, or other solvents such as 2-butanone or acetonitrile. Similarly, it is also possible to use mixtures of the above solvents. Preferably, ethanol is used.

Suitable bases for process steps (II) + (III) → (IV) and (VIII) + (IX) → (X) are sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium tert-butoxide and the like The alkali metal alkoxide, sodium or potassium hydride of any alkali metal hydride, sodium amide, amides such as lithium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or triethylamine, diisopropylethylamine, 1,5-diazabicyclo [4 .3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,4-diazabicyclo [2.2.2] octane (DA CO®) or phosphazene bases such as 1- [N-tert-butyl-P, P-di (pyrrolidin-1-yl) phosphorimidoyl] pyrrolidine or N ″ ′-tert-butyl-N, N , N ′, N′-tetramethyl-N ″-[tris (dimethylamino) -λ ⁵ -phosphanylidene] phosphoramidoimide. Preference is given to sodium ethoxide and potassium tert-butoxide.

  Here, the base is used in an amount of 1 to 5 mol, preferably 1.2 to 3 mol, per mol of the compound of formula (II) or (IX).

  The transformations (II) + (III) → (IV), (VI) + (III) → (VII) and (VIII) + (IX) → (X) are suitably performed in a microwave apparatus, usually from 0 ° C. It is carried out within the temperature range of + 150 ° C., preferably from + 20 ° C. to + 120 ° C. The reaction can be carried out at standard pressure, elevated pressure or reduced pressure (eg 0.05 to 0.5 MPa (0.5 to 5 bar)). Usually, standard pressure is used.

When X ¹ = OH, the transformation (IV) + (V) → (I-1) is performed under Mitsunobu conditions [a) Hughes, D. et al. L. "The Mitsunobu Reaction" Organic Reactions; John Wiley & Sons, Ltd, 1992, vol. 42, p. 335. b) Hughes, D.H. L. Org. Prep. Proceed. Int. 1996, 28, 127]. The Mitsunobu reaction is carried out using triphenylphosphine, or tri-n-butylphosphine, 1,2-bis (diphenylphosphino) ethane (DPPE), diphenyl (2-pyridyl) phosphine (Ph2P-Py), (p-dimethylaminophenyl). ) Diphenylphosphine (DAP-DP), tris (4-dimethylaminophenyl) phosphine (Tris-DAP), and suitable dialkyl azodicarboxylates such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), azo Di-tert-butyl dicarboxylate, N, N, N′N′-tetramethylazodicarboxamide (TMAD), 1,1 ′-(azodicarbonyl) dipiperidine (ADDP) or 4,7-dimethyl-3,5 , 7-Hexahydro-1,2,4 - carried out using the terazosin-3,8-dione (DHTD). Preferably, triphenylphosphine and diisopropyl azodicarboxylate (DIAD) are used.

  Examples of the inert solvent in Mitsunobu reaction (IV) + (V) → (I-1) include ethers such as tetrahydrofuran and diethyl ether, hydrocarbons such as benzene, toluene and xylene, and halohydrocarbons such as dichloromethane and dichloroethane. Or other solvents such as acetonitrile or dimethylformamide (DMF). It is likewise possible to use mixtures of the solvents mentioned. Preferably, THF or a mixture of THF and DMF is used.

  The Mitsunobu reaction (IV) + (V) → (I-1) is appropriately performed in a microwave apparatus, usually within a temperature range of −78 ° C. to + 180 ° C., preferably 0 ° C. to + 50 ° C. The conversion can be performed under standard pressure, increased pressure or reduced pressure (eg, 0.05 to 0.5 MPa (0.5 to 5 bar)).

When X ¹ is a suitable leaving group, the transformation (IV) + (V) → (I-1) is carried out under conditions for nucleophilic substitution. In that case, the inert solvent in process step (IV) + (V) → (I-1) is, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, benzene, toluene, xylene, hexane. Hydrocarbons such as cyclohexane or mineral oil fractions, halohydrocarbons such as dichloromethane, trichloromethane, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or dimethylformamide, dimethyl sulfoxide, N, N′-dimethylpropylene urea (DMPU), Other solvents such as N-methylpyrrolidinone (NMP), pyridine, acetone, 2-butanone or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preferably, acetonitrile in a mixture with acetonitrile, DMF or dimethylformamide is used.

  Suitable bases for process step (IV) + (V) → (I-1) are common inorganic bases. There are specially alkali metal or alkaline earth metal carbonates such as lithium carbonate, sodium, potassium, calcium or cesium, as appropriate, alkali metal iodides such as potassium iodide, sodium or potassium methoxide, sodium Or an alkali metal alkoxide such as potassium ethoxide or sodium or potassium tert-butoxide, an alkali metal hydride such as sodium or potassium hydride, an amide such as sodium amide, lithium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide. Preferably, potassium carbonate to which potassium iodide or sodium hydride is added is used.

  In this case, the base is usually used in an amount of 1 to 5 mol, preferably 1.2 to 3 mol, relative to 1 mol of the compound of the formula (IV).

  The conversion (IV) + (V) → (I-1) is appropriately performed in a microwave apparatus, usually within a temperature range of 0 ° C. to + 100 ° C., preferably + 20 ° C. to + 80 ° C. The reaction can be carried out at standard pressure, elevated pressure or reduced pressure (eg 0.05 to 0.5 MPa (0.5 to 5 bar)). Usually, standard pressure is used.

  Inert solvents in process step (VII) → (IV) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, carbonization such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions. Hydrogen or other solvents such as chlorobenzene, dimethylformamide, dimethyl sulfoxide, N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (NMP), pyridine, acetone, 2-butanone or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preferably, toluene is used.

  The conversion (VII) → (IV) is appropriately performed in a microwave apparatus, usually within a temperature range of 0 ° C. to + 150 ° C., preferably + 20 ° C. to + 120 ° C. The reaction can be carried out under standard pressure, elevated pressure or reduced pressure (eg, 0.05 to 0.5 MPa (0.5 to 5 bar)). Usually, standard pressure is used.

  Method step (X) + (XI) → (I−1) is similar to a transformation referred to in the literature as Chang-Ram coupling. Inert solvents in process step (X) + (XI) → (I-1) are ethers such as 1,4-dioxane or tetrahydrofuran, halohydrocarbons such as dichloromethane, trichloromethane, 1,2-dichloroethane, or Other solvents such as dimethylformamide (DMF), N-methylpyrrolidone (NMP), acetonitrile or dimethyl sulfoxide (DMSO). It is likewise possible to use mixtures of the solvents mentioned. Preferred is. When (XI) is a boronic acid ester or trifluoroborate, it is a mixture of acetonitrile and DMSO, or (XI) is dichloromethane when it is a boronic acid. In some cases it is advantageous to add molecular sieves.

  Suitable bases in process step (X) + (XI) → (I-1) are pyridine, pyridine derivatives such as DMAP or organic tertiary amines such as diisopropylethylamine or triethylamine. Preferred is. When (XI) is a boronic acid ester or trifluoroborate, it is triethylamine, or when (XI) is a boronic acid, it is pyridine.

  Suitable catalysts in process step (X) + (XI) → (I-1) are copper (II) salts, such as copper (II) acetate or copper (II) triflate, preferably copper (II) acetate. It is.

  Process step (X) + (XI) → (I-1) is carried out in air or in an oxygen atmosphere.

  Reaction (X) + (XI) → (I-1) is usually carried out in the temperature range of 0 ° C. to + 150 ° C., preferably at + 20 ° C. to + 80 ° C.

Acquisition of the compound of the formula (I-2) by hydrolysis of the ester group R ^1A of the compound (I-1) is carried out by treating the ester with an acid or a base in an inert solvent. The resulting salt is first converted to the free carboxylic acid by acid treatment. In general, the ester hydrolysis is preferably carried out with an acid.

  Suitable inert solvents for these reactions are water, diethyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetonitrile, acetic acid, dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the solvents mentioned. In the case of basic ester hydrolysis, a mixture of water and dioxane, tetrahydrofuran or acetonitrile is preferably used. In the case of hydrolysis of tert-butyl ester, the solvent used in the reaction with trifluoroacetic acid is preferably dichloromethane, and in the case of reaction with hydrogen chloride, preferably tetrahydrofuran, diethyl ether or dioxane. For the hydrolysis of other esters under acidic conditions, preference is given to acetic acid or a mixture of acetic acid and water.

  A suitable base is an alkali metal or alkaline earth metal bicarbonate such as sodium or potassium bicarbonate. Preference is given to sodium hydrogen carbonate.

  Suitable acids for ester hydrolysis are usually sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or these Add water as appropriate. Preference is given to hydrogen chloride or trifluoroacetic acid in the case of tert-butyl esters, and in the case of methyl and ethyl esters hydrochloric acid in a mixture with acetic acid and sulfuric acid in a mixture with acetic acid and water.

  The ester hydrolysis is usually performed within a temperature range of 0 ° C. to 180 ° C., preferably at + 20 ° C. to 120 ° C.

  These transformations can be performed under standard pressure, elevated pressure or reduced pressure (eg, 0.05 to 0.5 MPa (0.5 to 5 bar)). Generally, standard pressure is used in each case.

  The preparation of the compounds of the present invention can be illustrated by the following synthetic schemes (Schemes 1 to 3), by way of example.

Scheme 1

[A): 1. Triethylamine, ethanol, 80 ° C .; 2. Potassium tert-butoxide, 0 ° C. to 80 ° C .; b): K ₂ CO ₃ , KI, DMF;

Scheme 2

[A): triphenylphosphine, DIAD, THF / DMF 1: 1, 0 ° C. to RT; b): acetic acid / hydrochloric acid (2: 1), 120 ° C.].

Scheme 3

[A): i) 140 ° C., ii) sodium ethoxide, ethanol, 80 ° C .; b): Cu (OAc) ₂ , NEt ₃ , CH ₃ CN, DMSO. Molecular sieves, 80 ° C .; c): acetic acid / hydrochloric acid (2: 1), 120 ° C.].

  Compounds of formula (II), (III), (V), (VI), (VIII), (IX) and (XI) are either commercially available or known from the literature or similar to methods known from the literature Can be manufactured.

Further compounds of the invention may be prepared by conversion of the functional groups of the individual substituents, in particular those mentioned for R ³ , proceeding from the compounds of formula (I) obtained by the process described above. These transformations are performed by general methods known to those skilled in the art, as described in this experimental section, including, for example, nucleophilic and electrophilic substitution, oxidation, reduction, hydrogenation, transition metal catalysts. Such reactions include coupling reactions, elimination, alkylation, amination, esterification, ester hydrolysis, etherification, ether cleavage, carbon amide formation, and the introduction and elimination of temporary protecting groups. The conversion of the functional group can be explained by the following synthesis scheme (Scheme 4) by way of example.

Scheme 4

[A): 1. Ethanol, 80 ° C. Potassium tert-butoxide 80 ° C .; b): ( ^t BuOCO) ₂ O, DMAP, DMF / CH ₂ Cl ₂ , RT; c) triphenylphosphine, DIAD, THF / DMF 1: 1, 0 ° C. to RT; d) CF ₃ COOH, CH ₂ Cl ₂ , RT; e) CF ₃ CH ₂ CH ₂ Br, Cs ₂ CO ₃ , KI, DMF, 60 ° C .; f): Acetic acid / hydrochloric acid (2: 1), 120 ° C.].

  The compounds of the present invention have valuable pharmacological properties and can be used for the treatment and / or prevention of diseases in humans and animals.

  Since the compounds of the present invention are chymase inhibitors, they are suitable for the treatment and / or prevention of cardiovascular disorders, inflammatory disorders, allergic disorders and / or fibrotic disorders.

  In the context of the present invention, cardiovascular disorders or cardiovascular disorders are, for example, the following disorders: acute and chronic heart failure, arterial hypertension, coronary heart disease, stable and unstable angina, myocardial ischemia, myocardium Infarction, shock, atherosclerosis, cardiac hypertrophy, cardiac fibrosis, atrial and ventricular arrhythmias, transient and ischemic stroke, stroke, pre-eclampsia, inflammatory cardiovascular disorders, peripheral and cardiovascular disorders, Peripheral perfusion injury, arterial pulmonary hypertension, coronary artery and peripheral vasospasm, thrombosis, thromboembolic disease, edema development such as lung edema, brain edema, renal edema or heart failure-related edema, and post-thrombolytic treatment, transdermal Restenosis such as tubular angioplasty (PTA), transluminal coronary artery reconstruction (PTCA), heart transplantation and bypass surgery, and microvascular and macrovascular injury (vasculitis), reperfusion injury, arterial artery Fine venous thrombosis, microalbuminuria, myocardial dysfunction, endothelial dysfunction, high levels of fibrinogen and low-density LDL, is understood to mean a high concentration of active agent / inhibitor 1 (PAI-1).

  In the context of the present invention, the term “heart failure” includes more specific or related types of diseases such as acute decompensated heart failure, right heart failure, left heart failure, global failure, ischemic cardiomyopathy, dilated Cardiomyopathy, congenital heart defect, heart valve defect, heart valve related heart failure, mitral stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation, tricuspid stenosis, three Cusp insufficiency, pulmonary stenosis, pulmonary valve insufficiency, combined heart valve defect, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcohol-addictive myocardium There are also disorders, cardiac storage disorders, and diastolic and systolic heart failure.

  The compounds of the invention are further suitable for the prevention and / or treatment of multiple cystic kidney disease (PCKD) and abnormal ADH secretion syndrome (SIADH).

  Furthermore, the compounds of the invention are suitable for the treatment and / or prevention of kidney disorders, in particular acute and chronic renal dysfunction, and acute and chronic renal failure.

  In the context of the present invention, the term acute renal dysfunction refers to renal diseases that require and do not require dialysis, acute manifestations of renal failure and / or renal dysfunction, as well as basal or related kidney disorders For example, reduced renal blood flow, hypotension during dialysis, lack of volume (eg, dehydration, blood loss), shock, acute glomerulonephritis, hemolytic uremic syndrome (HUS), vascular rupture (arterial or venous thrombosis or embolism) ), Cholesterol embolism, acute Bens-Jones kidney in the case of plasmacytoma, immune renal disorders such as acute or subvesicular outflow obstruction, renal transplant rejection, immune complex induction Acute kidney injury characterized by nephropathy, tubule dilatation, hyperphosphatemia and / or the need for dialysis, eg Partial resection of kidney, forced dehydration, uncontrolled blood pressure increase due to malignant hypertension, cases of urinary tract obstruction and infection and amyloidosis, and systemic disorders with glomerular factors such as rheumatic immune system disorders Also included are, for example, lupus erythematosus, renal artery thrombosis, renal venous thrombosis, analgesic nephropathy and tubular acidosis, and X-ray contrast-induced and drug-induced acute interstitial kidney injury.

  In the context of the present invention, the term chronic renal dysfunction is a kidney disease that requires or does not require dialysis, chronic signs of renal failure and / or renal dysfunction, as well as underlying or related kidney disorders, such as Decreased renal blood flow, hypotension during dialysis, obstructive urinary tract disease, glomerulopathy, glomerular and tubular proteinuria, renal edema, hematuria, primary, secondary and chronic glomerulonephritis, membranous And membranoproliferative glomerulonephritis, Alport syndrome, glomerulosclerosis, tubulointerstitial disorders, nephropathy disorders such as primary and congenital kidney disease, kidney inflammation, immune kidney disorders such as kidney transplant rejection , Immune complex-induced nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome (diagnostic eg creatinine and / or Is an abnormal decrease in water excretion, an abnormal increase in blood levels of urea, nitrogen, potassium and / or creatinine, such as changes in the activity of kidney enzymes such as glutamyl synthase, changes in osmolality or urine volume, increases in microalbuminuria, Albuminuria, glomerular and arteriole lesions, tubule dilatation, hyperphosphatemia and / or need for dialysis)), and renal cell carcinoma, dehydration by forced diuresis after partial resection of the kidney Uncontrolled hypertension due to malignant hypertension, cases of urinary tract obstruction and infection and amyloidosis, and systemic disorders with glomerular factors such as rheumatoid-immune system disorders such as erythematous lupus and even renal artery stenosis Including renal artery thrombosis, renal venous thrombosis, analgesic nephropathy and tubular acidosis. In addition, there are X-ray contrast agent-induced and drug-induced chronic interstitial kidney injury, metabolic syndrome and dyslipidemia. The present invention further provides for the treatment of sequelae of renal dysfunction, such as pulmonary edema, heart failure, uremia, anemia, electrolyte imbalance (eg hyperkalemia, hyponatremia) and abnormalities in bone and carbohydrate metabolism and / or Includes the use of the compounds of the invention for prevention.

  In addition, the compounds of the present invention may be used for pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), α -1-antitrypsin deficiency (AATD), pulmonary fibrosis, emphysema (eg emphysema caused by smoking), cystic fibrosis (CF), acute coronary syndrome (ACS), myocardial inflammation (myocarditis) and other autoimmunity Cardiac disorders (epicarditis, endocarditis, valvitis, aortitis, cardiomyopathy), cardiogenic shock, aneurysm, sepsis (SIRS), multiple organ failure (MODS, MOF), kidney Suitable for treatment and / or prevention of inflammatory disorders, chronic intestinal disorders (IBD, Crohn's disease, UC), pancreatitis, peritonitis, rheumatoid disorders, inflammatory skin disorders and inflammatory ocular disorders .

  The compounds of the present invention further comprise a variety of severe asthma disorders with intermittent or persistent characteristics (refractory asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, drug-induced or dust-induced Asthma), various forms of bronchitis (chronic bronchitis, infectious bronchitis, eosinophilic bronchitis), obstructive bronchiolitis, bronchiectasis, pneumonia, idiopathic interstitial pneumonia, farmer's lung and related Treatment of disorders, coughs and colds (chronic inflammatory cough, iatrogenic cough), inflammation of the nasal mucosa (drug-related rhinitis, vasomotor rhinitis and seasonal allergic rhinitis such as hay fever) and polyps and / or Can be used for prevention.

  Furthermore, the compounds according to the invention are suitable for the treatment and / or prevention of visceral fibrosis, such as lung, heart, kidney, bone marrow, especially liver fibrosis, as well as dermatofibrosis and fibrotic ocular disorders. In the context of the present invention, the term “fibrosis” refers in particular to the following terms: liver fibrosis, cirrhosis, pulmonary fibrosis, endocardial myocardial fibrosis, cardiomyopathy, nephropathy, glomerulonephritis, interstitial Renal fibrosis, fibrotic damage caused by diabetes, myelofibrosis and similar fibrotic disorders, scleroderma, localized scleroderma, keloids, hypertrophic scars (even after surgery), nevi, diabetic Includes retinopathy and proliferative vitreoretinopathy.

  Furthermore, the compounds of the present invention are suitable for the suppression of postoperative scars caused by glaucoma surgery, for example.

  Furthermore, the compounds according to the invention can likewise be used cosmetically in the case of aging and hornifying skin.

  Furthermore, the compound of the present invention is used for dyslipidemia (hypercholesterolemia, hypertriglyceridemia, postprandial plasma triglyceride concentration, hypoalphalipoproteinemia, complex dyslipidemia), renal disorder and neuropathy), cancer (Skin cancer, brain tumor, breast cancer, bone marrow tumor, leukemia, liposarcoma, gastrointestinal tract, liver, pancreas, lung, kidney, urinary tract, prostate and reproductive tract cancer, and malignant tumors in the lymphoproliferative system such as Hodgkin lymphoma And non-Hodgkin lymphoma), gastrointestinal and abdominal disorders (glossitis, gingivitis, periodontal disease, esophagitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis, proctitis, anal pruritus, diarrhea , Celiac disease, hepatitis, chronic hepatitis, liver fibrosis, cirrhosis, pancreatitis and cholecystitis), skin disorders (allergic skin disorders, psoriasis, acne, eczema, neurodermatitis, various forms of dermatitis, and more Keratitis, bullous disease, vasculitis, cellulitis, subcutaneous lipohistitis, erythematous lupus, erythema, lymphoma, skin cancer, sweet syndrome, Weber-Christian syndrome, scar, hemorrhoid, moist), skeletal bones and joints Disorders, and even skeletal muscle disorders (various forms of arthritis, various forms of arthropathy, scleroderma and further disorders with inflammatory or immune components, paraneoplastic syndromes, eg in the case of rejection after organ transplantation, And can be used for the treatment and / or prevention of wound healing and angiogenesis, particularly in the case of chronic wounds.

  The compounds of formula (I) of the present invention further comprise ophthalmic disorders such as glaucoma, normal pressure glaucoma, high intraocular pressure and combinations thereof, age-related macular degeneration (AMD), dry or non-exudative AMD, wet or Exudative or neovascular AMD, choroidal neovascularization (CNV), retinal detachment, diabetic retinopathy, atrophic lesion to retinal pigment epithelium (RPE), hypertrophic lesion to retinal pigment epithelium (RPE), diabetic macular edema, retina Venous occlusion, choroidal retinal vein occlusion, macular edema, macular edema due to retinal vein occlusion, angiogenesis in the front of the eye, eg corneal neovascularization, eg keratitis, corneal transplantation or corneal transplantation, corneal neovascularization due to hypoxia Suitable for the treatment and / or prevention of long-term contact lens wear, pterygium conjunctiva, subretinal edema and intraretinal edema

  In addition, the compounds of formula (I) of the present invention may be used to produce intraocular pressure caused by traumatic anterior chamber bleeding, periorbital edema, postoperative viscoelasticity, endophthalmitis, corticosteroid use, pupillary block or idiopathic causes Used for the treatment and / or prevention of elevated and elevated intraocular pressure, and increased intraocular pressure after resection and preoperative conditions.

  The present invention further provides the use of the compounds of the invention for the treatment and / or prevention of disorders, in particular the disorders mentioned above.

  The present invention further provides the use of the compounds of the invention in the manufacture of a medicament for the treatment and / or prevention of disorders, in particular the disorders mentioned above.

  The present invention further provides a compound of the present invention for use in a method of treating and / or preventing heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, renal failure, nephropathy, visceral fibrosis and dermal fibrosis. provide.

  The compounds of the present invention can be used alone or in combination with other active ingredients as necessary. The invention therefore further provides a medicament comprising at least one compound of the invention and one or more further active ingredients, in particular for the treatment and / or prevention of the abovementioned disorders. Preferred examples of suitable active ingredient combinations include the following.

By way of example and preferably, compounds that inhibit the signaling cascade from the group of kinase inhibitors, in particular from the group of tyrosine kinases and / or serine / threonine kinase inhibitors;
Compounds that inhibit degradation and alteration of the extracellular matrix, by way of example and preferably, inhibitors of matrix metalloproteinases (MMPs), particularly stromelysin, collagenases, gelatinases and aggrecanases (especially MMPs in this context) -1, inhibitors of MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) and inhibitors of metalloelastase (MMP-12);
A compound that blocks the binding of serotonin to its receptor, by way of example and preferably an antagonist of the 5-HT _2b receptor;
Organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
NO-independent but heme-dependent soluble guanylate cyclase stimulators, such as the compounds described in WO00 / 06568, WO00 / 0669, WO02 / 430301 and WO03 / 095451 in particular;
NO and heme-dependent soluble guanylate cyclase activators, for example the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;
Prostacyclin analogs, by way of example and preferably iloprost, beraprost, treprostinil or epoprosterol;
Compounds that inhibit soluble epoxide hydrolase (sEH), such as N, N'-dicyclohexylurea, 12- (3-adamantan-1-yl-ureido) dodecanoic acid or 1-adamantan-1-yl-3- {5 -[2- (2-ethoxyethoxy) ethoxy] pentyl} urea;
Compounds that affect the energy metabolism of the heart, by way of example and preferably etomoxyl, dichloroacetate, ranolazine or trimetazidine;
Compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), for example inhibitors of phosphodiesterase (PDE) 1, 2, 3, 4 and / or 5, especially PDE5 Inhibitors such as sildenafil, vardenafil and tadalafil;
An antithrombotic agent, for example and preferably from the group of platelet aggregation inhibitors, anticoagulants or fibrinolysis-promoting substances;
Antihypertensive active ingredient, for example and preferably calcium antagonist, angiotensin AII antagonist, ACE inhibitor, vasopeptidase inhibitor, endothelin antagonist, renin inhibitor, α-receptor blocker, β-receptor blocker, mineralocorticoid From the group of receptor antagonists, and rho kinase inhibitors and diuretics;
Vasopressin receptor antagonists such as and preferably conivaptan, tolvaptan, lixivaptan, mozabaptan, satavaptan, SR-12463, RWJ676760 or BAY86-8050;
Bronchodilators, by way of example and preferably from the group of β-adrenergic receptor agonists, such as in particular the group of albuterol, isoproterenol, metaproterenol, terbutaline, formoterol or salmeterol, or anticholinergics From, for example, ipratropium bromide in particular;
Anti-inflammatory agents, by way of example and preferably from the group of glucocorticoids, for example prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone; and / or alter lipid metabolism Active ingredient, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors, by way of example and preferably HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-α, PPAR-γ and / or PPAR-δ agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors and lipoprotein (a) antagonists .

  In a preferred embodiment of the invention, the compounds of the invention are kinase inhibitors, by way of example and preferably bortezomib, caneltinib, erlotinib, gefitinib, imatinib, lapatinib, restaurinib, lonafamib, pegaptanib, peritinib, semafenib, sorafenib, sorafenib, , Tandutinib, Tipifarnib, Batalanib, Fasudil, Lonidamine, Leflunomide, BMS-3354825 or Y-27632.

  In a preferred embodiment of the invention, the compounds of the invention are used in combination with a serotonin receptor antagonist, by way of example and preferably PRX-08066.

Antithrombotic agents are preferably understood to mean compounds from the group of platelet aggregation inhibitors, anticoagulants or fibrinolysis-promoting substances. .
In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a platelet aggregation inhibitor such as by way of example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thrombin inhibitor such as by way of example and preferably ximelagatran, melagatran, bivalirudin or clexane.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a GPIIb / IIIa antagonist such as by way of example and preferably tirofiban or abciximab.

  In a preferred embodiment of the invention, the compounds of the invention comprise a factor Xa inhibitor, such as by way of example and preferably rivaroxaban, DU-176b, fidexaban, razakiban, fondaparinux, idraparinux, PMD-3112, YM -150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX9065a, DPC906, JTV803, SSR-126512 or SSR-128428.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a vitamin K antagonist such as by way of example and preferably coumarin.

  The antihypertensive agent is preferably a calcium antagonist, angiotensin AII antagonist, ACE inhibitor, endothelin antagonist, renin inhibitor, α-receptor blocker, β-receptor blocker, mineralocorticoid receptor antagonist, rho It is understood to mean a compound from the group of kinase inhibitors and diuretics.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a calcium antagonist such as by way of example and preferably nifedipine, amlodipine, verapamil or diltiazem.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an alpha-1 receptor blocker such as by way of example and preferably prazosin.

  In a preferred embodiment of the invention, the compound of the invention is a beta receptor blocker, by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, methylipranolol, It is administered in combination with nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, seriprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an angiotensin AII antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.

  In a preferred embodiment of the invention, the compounds according to the invention are used in combination with ACE inhibitors, by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril. Administered.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an endothelin antagonist such as by way of example and preferably bosentan, darsentan, ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with. Renin inhibitors, by way of example and preferably aliskiren, SPP-600 or SPP-800.
In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a mineralocorticoid receptor antagonist such as by way of example and preferably spironolactone or eplerenone.

  In a preferred embodiment of the invention, the compounds of the invention comprise a rho kinase inhibitor, by way of example and preferably fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095, It is administered in combination with SB-772077, GSK-269962A or BA-1049.

  In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a diuretic such as by way of example and preferably furosemide.

  Agents that alter lipid metabolism are preferably CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-α, PPAR Means a compound from the group of γ and / or PPAR-δ agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein (a) antagonists It is understood.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a CETP inhibitor such as by way of example and preferably torcetrapib (CP-529414), JJT-705 or CETP vaccine (Avant).

  In a preferred embodiment of the invention, the compounds of the invention are thyroid receptor agonists, by way of example and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS23425 or axityrom (CGS26214). Administered in combination.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with statins, by way of example and preferably with HMG-CoA reductase inhibitors from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin. The

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an ACAT inhibitor such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an MTP inhibitor such as by way of example and preferably implitapide, BMS-201038, R-103757 or JTT-130.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-γ agonist such as by way of example and preferably pioglitazone or rosiglitazone.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-δ agonist such as by way of example and preferably GW501516 or BAY685042.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamacueside.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipase inhibitor such as by way of example and preferably orlistat.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a polymeric bile acid adsorbent, such as by way of example and preferably cholestyramine, colestipol, colesolvam, cholestagel or colestimide.

  In a preferred embodiment of the invention, the compounds of the invention comprise a bile acid reabsorption inhibitor, for example and preferably an ASBT (= IBAT) inhibitor such as AZD-7806, S-8921, AK-105, BARI-1741. , SC-435 or SC-635.

  In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipoprotein (a) antagonist such as by way of example and preferably gemcabene calcium (CI-1027) or nicotinic acid.

  The present invention further provides a medicament comprising at least one compound of the invention together with one or more inert, non-toxic, pharmaceutically suitable excipients, as well as its use for the above purposes. .

  The compounds of the invention can act systemically and / or locally. In this regard, the compounds are administered in a suitable manner, for example oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, cutaneous, transdermal, conjunctival, otic route or as an implant or stent. can do.

  The compounds of the present invention can be administered in dosage forms suitable for these routes of administration.

  Suitable dosage forms for oral administration are those which act according to the prior art and release the compounds of the invention in a rapid and / or modified manner, and crystalline and / or amorphous and / or dissolved forms Containing a compound of the present invention, such as a tablet (a plain or coated tablet, eg, a gastric fluid resistant or delayed dissolution or insoluble coating that controls the release of the compound of the present invention), a tablet that disintegrates rapidly in the oral cavity or Film / oblate, film / lyophilizate or capsules (eg hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

  Parenteral administration can avoid the absorption phase (eg, venous route, arterial route, intracardiac route, intrathecal route or intralumbar route) or include absorption (eg, inhalation route, intramuscular route, Subcutaneous, intradermal, transdermal or intraperitoneal route). Suitable dosage forms for parenteral administration include injection and infusion formulations in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.

  For other routes of administration, suitable examples are inhaled drugs (powder inhalers, nebulizers, aerosols), nasal drops, solutions or sprays; tablets for tongue, sublingual or buccal administration, films / oblates or capsules, suppositories , Ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), fat-soluble suspensions, ointments, creams, transdermal therapeutic systems (eg, patches), emulsions, pastes, foams, sweat remover powders , Implant or stent.

  Oral and parenteral administration are preferred, especially oral, intravenous and inhalation administration.

  The compounds of the present invention can be converted into the above dosage forms. This can be done in a manner known per se by mixing with excipients suitable as inert and non-toxic medicaments. These excipients include carriers (eg, microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (eg, sodium dodecyl sulfate, polyoxy oleate) Sorbitan), binders (eg, polyvinylpyrrolidone), synthetic and natural polymers (eg, albumin), stabilizers (eg, antioxidants, eg, ascorbic acid), dyes (eg, inorganic pigments, eg, iron oxide), and flavoring agents and And / or odor correctors.

  In general, for parenteral administration, it has been found advantageous to administer an amount of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight to obtain effective results. ing. For oral administration, the dosage is about 0.01 to 100 mg / kg body weight, preferably about 0.01 to 20 mg / kg body weight, most preferably 0.1 to 10 mg / kg body weight.

  In spite of this, it may be necessary to deviate from the specified amount depending on the body weight, administration route, individual responsiveness to the active ingredient, formulation type, and time or interval of administration. For example, in some cases, an amount less than the aforementioned minimum amount may be sufficient, while in other cases the above upper limit needs to be exceeded. When administering larger amounts, it may be desirable to divide the amount into several individual doses over the day.

  The following working examples illustrate the present invention. The present invention is not limited to these examples.

  The percentages in the tests and examples below are, unless indicated otherwise, percentages by weight and parts are parts by weight. Solvent ratios, dilution ratios and concentration data in liquid / liquid solutions are volume based in each case unless otherwise noted.

A. Example
abbreviation:
Ac: Acetyl aq. : Aqueous system, aqueous solution br. d: Wide double line (NMR)
br. m: Wide multiple line (NMR)
br. s: Wide single line (NMR)
br. t: Wide triplet (NMR)
c: Concentration cat. : Catalyst TLC: Thin layer chromatography DCI: Direct chemical ionization (by MS)
dist. : Distillation DIAD: Diisopropyl azodicarboxylate DIEA: N, N-diisopropylethylamine DMAP: 4-N, N-dimethylaminopyridine DMF: Dimethylformamide DMSO: Dimethylsulfoxide DSC: Differential scanning calorimetry EDC: N '-(3-Dimethyl Aminopropyl) -N-ethylcarbodiimide hydrochloride ee: enantiomeric excess ent: enantiomerically pure, enantiomer eq. : Equivalent ESI: Electrospray on (in MS)
Et: Ethyl GC-MS: Gas chromatography coupled mass spectrometry h: Time HATU: O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate HOBt : 1-hydroxy-1H-benzotriazole hydrate HPLC: high pressure high performance liquid chromatography conc. : Concentration LC-MS: Liquid chromatography coupled mass spectrometry Me: Methyl min: Min MPLC: Medium pressure liquid chromatography MS: Mass spectrometry MTBE: Methyl tert-butyl ether NMR: Nuclear magnetic resonance spectroscopy Pd / C: Palladium / activated carbon Ph : Phenyl PyBOP: Benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate quant. : Quantitative (in the case of yield)
rac: racemic, racemic RT: room temperature Rt: retention time (by HPLC)
m. p. : Melting point tBu: tert-butyl tert: tertiary TFA: trifluoroacetic acid TFAA: trifluoroacetic anhydride THF: tetrahydrofuran TPPO: triphenylphosphine oxide UV: ultraviolet spectroscopic analysis cf. : Reference v / v: Volume ratio (in the case of a solution).

HPLC, GC-MS and LC-MS methods
Method 1 : Apparatus: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLC HSS T3 1.8 μm 50 × 1 mm; Eluent A: 1 liter water + 0.25 mL 99% formic acid, Eluent B: 1 liter acetonitrile + 0.25 mL 99% Formic acid; Gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A; Oven: 50 ° C .; Flow rate: 0.40 mL / min; UV detection: 210-400 nm.

Method 2 : MS instrument type: Waters (Micromass) Quattro Micro; HPLC instrument type: Agilent 1100 Series; Column: Thermo Hypersil GOLD 3μ 20 × 4 mm; Eluent A: 1 liter water + 0.5 mL 50% formic acid, eluent B: 1 Liter acetonitrile + 0.5 mL 50% formic acid; gradient: 0.0 min 100% A → 3.0 min 10% A → 4.0 min 10% A → 4.01 min 100% A (flow rate 2.5 mL) → 5 0.00% 100% A; Oven: 50 ° C .; Flow rate: 2 mL / min; UV detection: 210 nm.

Method 3 : Apparatus: Micromass Quattro Premier equipped with Waters UPLCAcquity; Column: Thermo Hypersil GOLD 1.9 μm 50 × 1 mm; Eluent A: 1 liter water + 0.5 mL 50% formic acid, eluent B: 1 liter acetonitrile + 0.5 mL 50% Formic acid; Gradient: 0.0 min 90% A → 0.1 min 90% A → 1.5 min 10% A → 2.2 min 10% A Oven: 50 ° C .; Flow rate: 0.33 mL / min; UV detection : 210 nm.

Method 4 : Apparatus: Micromass Quattro Premier equipped with Waters UPLCAcquity; Column: Thermo Hypersil GOLD 1.9 μm 50 × 1 mm; Eluent A: 1 liter water + 0.5 mL 50% formic acid, eluent B: 1 liter acetonitrile + 0.5 mL 50% Formic acid; Gradient: 0.0 min 97% A → 0.5 min 97% A → 3.2 min 5% A → 4.0 min 5% A Oven: 50 ° C .; Flow rate: 0.3 mL / min; UV detection : 210 nm.

Method 5 (LC-MS): Apparatus: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLC HSS T3 1.8 μm 30 × 2 mm; Eluent A: 1 liter water + 0.25 mL 99% formic acid, Eluent B: 1 liter Acetonitrile + 0.25 mL 99% formic acid; Gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A Oven: 50 ° C .; Flow rate: 0.60 mL / min; UV detection: 208 -400 nm.

Method 6 (GC-MS): Equipment: Micromass GCT, GC6890; Column: Restek RTX-35, 15 m × 200 μm × 0.33 μm; Constant flow helium: 0.88 mL / min; Oven: 70 ° C .; Inlet: 250 ° C. Gradient: 70 ° C., 30 ° C./min→310° C. (hold for 3 minutes).

Method 7 (Preparative HPLC): Column: Reprosil C18, 10 μm, 250 mm × 30 mm. Eluent A: 0.1% aqueous formic acid, eluent B: acetonitrile; flow rate: 50 mL / min; program: 0 to 6 minutes: 90% A / 10% B; gradient from 6 minutes to 27 minutes: 95% B; 27-38 min 95% B; gradient from 38 min to 39 min 10% B; 39 min to 43 min (end): 60% A / 40% B. Some variation in slope is possible.

Method 8 (Preparative HPLC): Column: Reprosil C18, 10 μm, 250 mm × 30 mm. Eluent A: 0.1% formic acid aqueous solution, eluent B: methanol; flow rate: 50 mL / min; program: 0 to 4.25 min: 60% A / 40% B; 4.25 to 4.50 min: 60 Slope from 4.50 min to 17 min 100% B; 17 min to 19.50 min 100% B; 19.50 min to 19.75 min 40% B gradient; 19.75 to 22 min (End): 60% A / 40% B. Some variation in slope is possible.

Method 9 (Preparative HPLC): Column: Sunfire C18, 5 μm, 250 mm × 20 mm. Eluent methanol / TFA 1% aqueous solution 50/50; flow rate: 25 mL / min; detection 210 nm, temperature 40 ° C.

Method 10 (Preparative HPLC): Column: Sunfire C18, 5 μm, 250 mm × 20 mm. Eluent acetonitrile / TFA 1% aqueous solution 55/45; flow rate: 25 mL / min; detection 210 nm, temperature 40 ° C.

Method 11 : (Preparative HPLC): Column: Reprosil C18, 10 μm, 250 mm × 40 mm. Eluent A: 0.1% formic acid aqueous solution, eluent B: acetonitrile; flow rate: 50 mL / min. Program: 0-6 minutes: 90% A / 10% B; gradient to 6-40 minutes: 95% B; 40-53 minutes: 5% A / 95% B; 53.01-54 minutes: 10% B Slope to 54; 01-57 min: 90% A / 10% B.

Method 12 (Chiral Preparative HPLC): Daicel Chiralpak AD-H 250 mm × 20 mm column; flow rate: 20 mL / min; eluent: isopropanol / ethanol / isohexane 15:15:70 (volume ratio); detector 230 nm.

Method 13 (Chiral Analytical HPLC): Daicel Chiralpak AD-H 5 μm column, 250 mm × 4.6 mm; temperature 30 ° C .; flow rate: 1 mL / min; eluent: isopropanol / ethanol / isohexane 15:15:70 (volume ratio); Detector 220 nm.

Method 14 (Chiral Analytical HPLC): Daicel Chiralpak AS-H 5 μm column, 250 mm × 4.6 mm; temperature 30 ° C .; flow rate: 1 mL / min; eluent: ethanol / isohexane 50:50, 1% water and 0.2% Add trifluoroacetic acid; detector 220 nm.

Method 15 (Preparative HPLC): Same as Method 7 except using Chromatorex C18 250 mm × 30 mm column.

Method 16 (Chiral Preparative HPLC): Daicel Chiralpak AZ-H 250 mm × 20 mm column; flow rate: 20 mL / min; eluent: ethanol / isohexane 50:50 (volume ratio), 1% water and 0.2% trifluoroacetic acid Added; detector 230 nm.

Method 17 (Chiral Analytical HPLC): Daicel Chiralpak AZ-H 5 μm column, 250 mm × 4.6 mm; temperature 40 ° C .; flow rate: 1 mL / min; eluent: ethanol / isohexane 50:50 (volume ratio), water and 0. 1% addition of 2% trifluoroacetic acid; detector 220 nm.

Method 18 (Chiral Preparative HPLC): Daicel Chiralpak AD-H 250 mm × 20 mm column; flow rate: 20 mL / min; eluent: isopropanol / isohexane 50:50 (volume ratio), 1% water and 0.2% trifluoroacetic acid Added; detector 230 nm.

Method 19 (Chiral Analytical HPLC): Daicel Chiralpak AD-H 5 μm column, 250 mm × 4.6 mm; temperature 30 ° C .; flow rate: 1 mL / min; eluent: isopropanol / isohexane 50:50 (volume ratio), 1% water and 0.2% trifluoroacetic acid added; detector 220 nm.

Method 20 (Chiral Preparative HPLC): Daicel Chiralpak AD-H 250 mm × 20 mm column; flow rate: 20 mL / min; eluent: ethanol / isohexane 70:30 (volume ratio), 1% water and 0.2% trifluoroacetic acid Added; detector 230 nm.

Method 21 (Chiral Analytical HPLC): Daicel Chiralpak AD-H 5 μm column, 250 mm × 4.6 mm; temperature 40 ° C .; flow rate: 1 mL / min; eluent: ethanol / isohexane 70:30 (volume ratio), 1% water and 0.2% trifluoroacetic acid added; detector 220 nm.

Method 22 (Preparative HPLC): Column: Sunfire C18, 5 μm, 250 mm × 20 mm. Eluent acetonitrile / water 60:40; flow rate: 25 mL / min; detection 210 nm, temperature 40 ° C.

Method 24 (Preparative HPLC): Column: Sunfire C18, 5 μm, 75 mm × 30 mm. Eluent acetonitrile / 0.05% aqueous TFA solution 1:99 to 2.25 min, then acetonitrile / 1% aqueous TFA solution 95: 5; flow rate: 60 mL / min; detection 210 nm, temperature 40 ° C.

Method 25 (Chiral Analytical HPLC): Daicel Chiralpak AD-H 5 μm column, 250 mm × 4.6 mm; temperature 30 ° C .; flow rate: 1 mL / min; eluent: isopropanol / isohexane 5:95 (volume ratio); detector 220 nm.

The method 26: MS, apparatus: Thermo Fisher-Scientific DSQ; chemical ionization; reaction gas NH _3; Source temperature: 200 ° C.; ionization energy 70 eV.

Method 27 (chiral analytical HPLC): Daicel Chiralpak AD-H 5 μm column, 250 mm × 4.6 mm; temperature 30 ° C .; flow rate: 1 mL / min; eluent: isopropanol / ethanol / isohexane 25:25:50 (volume ratio); Detector 220 nm.

Method 28 (LC-MS): MCW_SQ-HSST3_long Apparatus: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLC HSS T3 1.8 μm 50 × 1 mm; Eluent A: 1 liter water + 0.25 mL 99% formic acid, eluent B 1 liter acetonitrile +0.25 mL 99% formic acid; gradient: 0.0 min 95% A → 6.0 min 5% A → 7.5 min 5% A; oven: 50 ° C .; flow rate: 0.35 mL / min; UV detection: 210-400 nm.

Method 29 (Chiral Preparative HPLC): Daicel Chiralpak IC 5 μm column, 250 mm × 20 mm; flow rate: 20 mL / min; temperature 25 ° C .; detector: 220 nm; eluent: acetonitrile / MTBE 50:50 (volume ratio).

Method 30 (chiral analytical HPLC): Daicel Chiralpak IC 5 μm column, 250 mm × 4.6 mm; flow rate: 1 mL / min; temperature 30 ° C .; detector: 220 nm; eluent: acetonitrile / MTBE 50:50 (volume ratio).

Method 31 (Chiral Preparative HPLC): Daicel Chiralpak IA 5 μm column, 250 mm × 20 mm; flow rate: 20 mL / min; temperature 30 ° C .; detector: 285 nm; eluent: acetonitrile / MTBE 50:50 (volume ratio).

Method 32 (Chiral Analytical HPLC): Daicel Chiralpak IA 5 μm column, 250 mm × 4.6 mm; flow rate: 1 mL / min; temperature 30 ° C .; detector: 285 nm; eluent: acetonitrile / MTBE 50:50 (volume ratio).

Method 33 (Chiral Preparative HPLC): Daicel Chiralpak IA 5 μm column, 250 mm × 20 mm; flow rate: 20 mL / min; temperature 30 ° C .; detector: 285 nm; eluent: acetonitrile / MTBE 20:80 (volume ratio).

Method 34 (chiral analytical HPLC): Daicel Chiralpak IA 5 μm column, 250 mm × 4.6 mm; flow rate: 1 mL / min; temperature 30 ° C .; detector: 285 nm; eluent: acetonitrile / MTBE 50:50 (volume ratio).

Raw material compounds and intermediates:
Example 1A
5-Amino-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride

  1,3-dimethyl-5-nitro-1,3-dihydro-2H-benzimidazol-2-one (preparation: WO2007 / 120339, Example 2, page 33) in 1790 mL of ethanol 33.2 g (160 mmol) ( Partially dissolved) was hydrogenated in the presence of 8.8 g of palladium catalyst (10% activated carbon support, wet with 50% water) at room temperature and hydrogen pressure of 1 atm. The raw material dissolved during the reaction. After complete conversion (6 hours), the catalyst was removed by filtration through diatomaceous earth. The filtrate was mixed with 45 mL of hydrogen chloride solution (4N solution in dioxane) and then concentrated to dryness on a rotary evaporator. The residue was further dried under HV. This gave 31.8 g (91% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.18 min; m / z = 178 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.33 (s, 3H), 3.34 (s, 3H), 7.06 to 7.15 (m, 2H), 7. 23 (d, 1H), 10.29 (br.s, 3H).

Example 2A
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl

  First, 52.80 g (247.1 mmol) of the compound from Example 1A and ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate (for preparation, Senda, Shigeo; Hirota, Kosaku; Notani, Jioji, Chemical & Pharmaceutical Bulletin (1972), 20 (7), 1380-8) 64.07 g (247.1 mmol) was placed in 2 liters of ethanol and 51.7 mL (370.7 mmol) of triethylamine was added. The thick suspension formed was heated to reflux temperature for 1.5 hours to form a clear solution. After cooling slightly (about 60 ° C.), 27.73 g (247.1 mmol) of potassium tert-butoxide was added. The reaction mixture was heated again to reflux temperature and stirred at this temperature for an additional 7 hours. After cooling to room temperature, about half of the solvent was removed on a rotary evaporator. The concentrated reaction mixture was poured into 7.5 liters of 1N hydrochloric acid. The precipitated solid was filtered, washed with 800 mL of water and dried under HV. This gave 71.7 g (85% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.63 min; m / z = 345 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 2H), 3.30 (s, 3H), 3.37 (s, 3H), 4.17 (q, 2H), 7.19 (dd, 1H), 7.25 (d, 1H), 7.37 (d, 1H), 8.26 (s, 1H).

Example 3A
1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3-dihydro-2H-benzimidazol-2-one

  First, 3.16 g (12.44 mmol) of 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane and dibenzoyl peroxide 43 mg (purity 70%, 0.124 mmol) was placed in 12 mL of acetonitrile at room temperature, and 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one (treated with hydrogen chloride). 1.47 g (8.3 mmol) and 1.48 mL (12.44 mmol) tert-butyl nitrite were added, except according to the procedure described in Example 1A. The reaction mixture was stirred at room temperature overnight. The solvent was removed on a rotary evaporator. The residue was dissolved in a small amount of dichloromethane, diatomaceous earth was added to the solution, and the solution was concentrated again to dryness on a rotary evaporator. The residue was purified using a silica gel cartridge (eluent: cyclohexane / ethyl acetate 2: 1 to 1: 1). Fractions containing product were concentrated on a rotary evaporator. The residue was stirred with 10 mL of pentane and the precipitated solid was filtered, washed with pentane and dried under HV. This gave 860 mg of the title compound (94% purity). Additional silica gel chromatography with the mother liquor yielded 230 mg of additional title compound (overall yield: 43% of theory).

LC-MS (Method 1): Rt = 0.95 min; m / z = 289 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.30 (s, 12H), 3.33 (s, partly under water signal, 3.35 (s, 3H), 7.16 (d, 1H), 7.35 (s, 1H), 7.44 (d, 1H).

Example 4A
1- (2-Chloro-3,6-difluorobenzyl) urea

  First, 1.50 g (8.44 mmol) of 2-chloro-3,6-difluorobenzylamine and 2.03 g (33.8 mmol) of urea were placed in 4 mL of water. After adding 90 μL (about 1 mmol) of concentrated hydrochloric acid, the reaction mixture was heated to reflux for 3.5 hours. After cooling to room temperature, 100 mL of water was added and the mixture was stirred for 30 minutes. The precipitated crystals were filtered and washed twice with a small amount of water, then with a small amount of MTBE and dried under HV. This gave 1.16 g (62% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.79 min; m / z = 221 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 4.34 (dd, 2H), 5.51 (s, 2H), 6.36 (t, 1H), 7.26-7. 34 (m, 1H), 7.39-7.48 (m, 1H).

Example 5A
Ethyl 3- (2-chloro-3,6-difluorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  Suspension of 1.16 g (5.25 mmol) of 1- (2-chloro-3,6-difluorobenzyl) urea from Example 4A and 1.59 mL (7.86 mmol) of diethyl ethoxymethylenemalonate in ethanol (2 mL) The solution was heated to 140 ° C. (bath temperature) and stirred at this temperature overnight. The reaction mixture cooled to room temperature was dissolved in about 6 mL of ethanol, 535 mg (7.9 mmol) of sodium ethoxide was added, and the mixture was heated to reflux again. After 2 days, an additional 0.5 equivalent of base was added and the mixture was heated to reflux temperature for an additional 3 days. After cooling to room temperature, the mixture was acidified with 1M hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated on a rotary evaporator. The residue was stirred with ethyl acetate / MTBE 1: 1. The solid was filtered, washed with MTBE and dried under HV. This gave 851 mg (45% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.79 min; m / z = 345 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 4.16 (q, 2H), 5.13 (s, 2H), 7.20-7. 29 (m, 1H), 7.38-7.46 (m, 1H), 8.20 (s, 1H), 11.94-12.05 (m, 1H).

Example 6A
1- (3-Chloro-2-methylbenzyl) urea

  The reaction time was 6 hours, and the title compound was produced and purified as in Example 4A. Starting from 2.00 g (12.85 mmol) of 3-chloro-2-methylbenzylamine and 3.08 g (51.40 mmol) of urea, this gave 2.36 g (92% of theory) of the title compound. .

LC-MS (Method 1): Rt = 0.72 min; m / z = 199 (M + H) ^<+> .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.29 (s, 3H), 4.19 (d, 2H), 5.53 (s, 2H), 6.36 (t, 1H), 7.14-7.22 (m, 2H), 7.28-7.35 (m, 1H).

Example 7A
Ethyl 3- (3-chloro-2-methylbenzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  A suspension of 2.36 g (11.88 mmol) of 1- (3-chloro-2-methylbenzyl) urea from Example 6A and 3.60 mL (17.82 mmol) of diethyl ethoxymethylenemalonate in ethanol (3 mL). The solution was heated to 140 ° C. (bath temperature) and the solution formed after about 3 hours was further stirred at this temperature overnight. The mixture cooled to room temperature was dissolved in 20 mL of ethanol, 1.21 g (17.8 mmol) of sodium ethoxide was added, and the mixture was heated to reflux again for 1.5 hours. After cooling to room temperature, the reaction mixture was added dropwise to 100 mL of ice-cold 0.5M hydrochloric acid. The precipitated solid was filtered, washed with MTBE and dried under HV. This gave 2.20 g (57% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.90 min; m / z = 323 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (t, 3H), 2.40 (s, 3H), 4.17 (q, 2H), 4.96 (s, 2H), 6.85 (d, 1H), 7.13 (t, 1H), 7.33 (d, 1H), 8.25 (s, 1H), 12.06 (br.s, 1H).

Example 8A
1- [2,3-Bis (trifluoromethyl) phenyl] methanamine

  First, 69.38 mL (69.38 mmol) of borane-THF complex (1.0 M) was added under argon, and the reaction mixture was cooled to 0 ° C. Next, 2,3-bis (trifluoromethyl) benzonitrile (for production see Zhurn Organicichekoi Kimii 1973, 9 (5), 1019-1024, 1046-1050) 5.53 g (23.13 mmol) of THF (50 mL) in solution was added and heated to reflux for 3 hours. The reaction mixture was cooled to 0 ° C., acidified with 1N hydrochloric acid, and concentrated under reduced pressure. The residue was diluted with water and the aqueous phase was washed 3 times with dichloromethane. The pH was then adjusted to 14 using 1N sodium hydroxide solution, the mixture was extracted three times with dichloromethane, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 4.07 g (70% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.49 min; MS (ESI cation): m / z = 244 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.99 (br.s, 2H), 3.90-3.97 (m, 2H), 7.83-7.92 (m 2H), 8.17-8.23 (m, 1H).

Example 9A
1- [2,3-Bis (trifluoromethyl) benzyl] urea

  First, 780 mg (3.21 mmol) of 1- [2,3-bis (trifluoromethyl) phenyl] methanamine from Example 8A and 771 mg (12.83 mmol) of urea were placed in 1.3 mL of water, and 34 μL of concentrated hydrochloric acid was added. (0.41 mmol) was added dropwise and the mixture was heated to reflux for 3 hours. Next, it diluted with water (100 mL) at room temperature, and stirred for 30 minutes. The solid formed was filtered, washed twice with water and diethyl ether, respectively, and dried under high vacuum. This gave 541 mg (59% of theory) of the target compound.

LC-MS (Method 1): Rt = 0.85 min; MS (ESI cation): m / z = 287 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 4.40-4.45 (m, 2H), 5.72 (s, 2H), 6.57-6.63 (m, 1H ), 7.86-7.90 (m, 2H), 7.91-7.95 (m, 1H).

Example 10A
Ethyl 3- [2,3-bis (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  A mixture of 2.01 g (7.04 mmol) of 1- [2,3-bis (trifluoromethyl) benzyl] urea from Example 9A and 2.13 mL (10.60 mmol) of diethyl (ethoxymethylene) malonate was counter-argon. The mixture was stirred for 4 days at 140 ° C. in an air stream. The reaction mixture was then diluted with ethanol (20 mL), then 0.72 g (10.60 mmol) of sodium ethoxide was added and the mixture was heated to reflux for an additional 2.5 hours. The mixture brought to room temperature was added dropwise to ice-cold hydrochloric acid (400 mL, 0.5 M) and the solid formed was filtered. The filter residue was stirred with MTBE, filtered and dried under high vacuum. This gave 1.92 g (67% of theory) of the target compound.

LC-MS (Method 1): Rt = 0.99 min; MS (ESI cation): m / z = 411 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (t, 3H), 4.18 (q, 2H), 5.17 (br.s, 2H), 7.52 ( d, 1H), 7.76-7.83 (m, 1H), 7.92-7.98 (m, 1H), 8.29 (s, 1H), 12.15 (br.s, 1H) .

Example 11A
N-benzyl-4- (trifluoromethyl) indan-1-amine (racemic)

  To a mixture of 15.40 g (0.075 mol) 4- (trifluoromethyl) -1-indanone and 9.78 mL (0.090 mol) benzylamine in dichloromethane (462 mL) was added 33.0 mL titanium (IV) isopropoxide ( 0.112 mol) was added and the mixture was stirred at room temperature for 1 hour. Next, at 0 ° C., 5.65 g (0.149 mol) of sodium borohydride was added in small portions and the mixture was stirred at room temperature overnight. For workup, the mixture was then dripped into water and a vigorous gas evolved. The mixture was then further diluted with water and dichloromethane (500 mL each), the organic phase was dried over sodium sulfate, filtered and the filtrate concentrated. The crude product thus obtained was chromatographed on silica gel (petroleum ether / ethyl acetate, 10: 1). This gave 12.80 g (58% of theory) of the target compound.

LC-MS (Method 1): Rt = 0.80 min; MS (ESI cation): m / z = 292 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.81-1.93 (m, 1H), 2.31-2.42 (m, 1H), 2.57-2.65 (M, 1H), 2.81-2.93 (m, 1H), 3.04-3.15 (m, 1H), 3.72-3.85 (m, 2H), 4.14-4 .22 (m, 1H), 7.19-7.25 (m, 1H), 7.32 (t, 2H), 7.37-7.44 (m, 3H), 7.53 (d, 1H) ), 7.68 (d, 1H).

Example 12A
4- (Trifluoromethyl) indan-1-amine (racemic)

  First, 9.70 g (0.032 mol) of N-benzyl-4- (trifluoromethyl) indan-1-amine from Example 11A is placed in 230 mL of THF and then palladium (10% activated carbon supported product). 00 g was added and the mixture was hydrogenated at room temperature under atmospheric hydrogen overnight. The mixture was then filtered through diatomaceous earth and the filtrate was concentrated. This gave 6.40 g (98% of theory) of the crude product, which was converted without further purification.

LC-MS (Method 1): Rt = 0.56 min; MS (ESI cation): m / z = 202 (M + H) ⁺ .

Example 13A
1- [4- (Trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] urea (racemic)

  First, 6.40 g (0.03 mol) 4- (trifluoromethyl) indan-1-amine from Example 12A and 9.55 g (0.159 mol) urea were placed in 25 mL water and 0.34 mL concentrated hydrochloric acid. (0.004 mol) was added dropwise and the mixture was heated to reflux for 3 hours. The mixture was diluted with water (100 mL) at room temperature and stirred for 30 minutes. The formed solid was filtered, washed with water and dried under high vacuum. The crude product was recrystallized by stirring with diethyl ether (50 mL). This gave 4.60 g (59% of theory) of the target compound.

LC-MS (Method 1): Rt = 0.83 min; MS (ESI cation): m / z = 245 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.7-1-1.82 (m, 1H), 2.39-2.49 (m, 1H), 2.84-2.96 (M, 1H), 3.00-3.11 (m, 1H), 5.12 (q, 1H), 5.53 (s, 2H), 6.42 (d, 1H), 7.39- 7.45 (m, 1H), 7.53 (dd, 2H).

Example 14A
(S) -4-Trifluoromethylindan-1-ol

  4-Trifluoromethyl-1-indanone 55.7 g (278.3 mmol), 194 mL (1.391 mol) triethylamine and RuCl (p-cymene) [(S, S) -TsDPEN] (CAS number: 192139-90-5) IUPAC name: (S, S) -N- (p-toluenesulfonyl) -1,2-diphenylethanediamino (chloro) [1-methyl-4- (propan-2-yl) benzene] ruthenium (II)) A solution of 1.60 g (2.50 mmol) in dichloromethane (258 mL) was heated to 35 ° C. under argon and 52.5 mL (1.391 mol) of formic acid was slowly added at this temperature (addition time about 40 minutes). ). In the middle of this, the temperature of the reaction mixture rose to 42 ° C. When the addition was complete, the mixture was stirred at 38 ° C. for an additional 2 hours. All volatile components were removed on a rotary evaporator under HV. The residue was then dissolved in a small amount of dichloromethane and purified using 1 kg of silica gel (eluent: first cyclohexane / ethyl acetate 5:13 liter, then cyclohexane / ethyl acetate 1:16 liter). Appropriate fractions were concentrated on a rotary evaporator and the product was dried under HV. This gave 51.2 g (90% of theory) of the title compound.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.76-1.91 (m, 1H), 2.40 (ddt, 1H), 2.86 (dt, 1H), 3. 01-3.13 (m, 1H), 5.09 (q, 1H), 5.45 (d, 1H), 7.38-7.48 (m, 1H), 7.55 (d, 1H) 7.62 (d, 1H).

  Chiral analytical HPLC (Method 25): Rt = 7.49 min; 99% ee.

Example 15A
(R) -4-Trifluoromethylindan-1-ol

  Analogously to Example 14A, 5 g (25.0 mmol) of 4-trifluoromethyl-1-indanone was added to RuCl (p-cymene) [(R, R) -TsDPEN] (CAS number: 192139-92-7; IUPAC Name: (R, R) -N- (p-toluenesulfonyl) -1,2-diphenylethanediamino (chloro) [1-methyl-4- (propan-2-yl) benzene] ruthenium (II)) 143 mg ( In the presence of 0.225 mmol). This gave 4.60 g (91% of theory) of the title compound.

GC-MS (Method 6): Rt = 3.43 min; MS (CI-cation): m / z = 202 (M) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 1.94 (brd, 1H), 1.96-2.05 (m, 1H), 2.55 (dddd, 1H), 2.91- 3.04 (m, 1H), 3.19-3.30 (m, 1H), 5.27 (q, 1H), 7.32-7.38 (m, 1H), 7.53 (d, 1H), 7.60 (d, 1H).

Chiral analytical HPLC (Method 25): Rt = 6.51 min; ee about 96%.
Example 16A
5-Amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

  First, 2.43 g (12.6 mmol) of 1-methyl-5-nitro-1,3-dihydro-2H-benzimidazol-2-one [synthesis as described in US Pat. No. 6,114,532] is added to a THF / methanol mixture. (1: 2) Into 78.0 mL, 134 mg (0.13 mmol) of palladium (10% activated carbon supported product) was added, and the mixture was hydrogenated at standard hydrogen pressure overnight. The reaction mixture was then filtered through diatomaceous earth, the residue was washed with THF, and the filtrate was concentrated. This gave 1.89 g (92% of theory) of the target compound.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.16 (s, 3H), 4.66-4.71 (m, 2H), 6.25 (dd, 1H), 6. 28 (d, 1H), 6.71 (d, 1H), 10.39 (s, 1H).

Example 17A
5-Fluoro-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one

  First, 5.0 mL of DMF was added at 0 ° C. under argon, and 318 mg (7.96 mmol) of sodium hydride (60% suspension in mineral oil) was added. Next, 5-fluoro-1-methyl-1,3-dihydro-2H-benzimidazol-2-one [US2010 / 0305102, page 28, synthesis described in Example 26.3] 881 mg (5.30 mmol) of A solution in DMF (5.0 mL) was added dropwise and the reaction mixture was stirred for 30 minutes. Thereafter, 0.43 mL (6.90 mmol) of iodomethane was added dropwise and the mixture was stirred at room temperature overnight. Then sodium hydride (1.0 eq) was added again at 0 ° C., the mixture was stirred for a further 15 min and finally iodomethane (1.0 eq) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, then water (100 mL) was added and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and the filtrate was concentrated. The crude product so obtained was purified by flash silica gel chromatography (cyclohexane / ethyl acetate, gradient 7: 1 to 4: 1). This gave 672 mg (69% of theory) of the target compound.

LC-MS (Method 1): Rt = 0.69 min; MS (ESI cation): m / z = 181 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.33 (s, 3H), 3.3 (s, hidden by water signal), 6.85-6.93 (m 1H), 7.09-7.18 (m, 2H).

Example 18A
5-Fluoro-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzimidazol-2-one

  First, 670 mg (3.72 mmol) of 5-fluoro-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one from Example 17A was added to THF 3.5 mL at 0 ° C. under argon. Put it in. Then, nitric acid (65%) 0.24 mL (3.72 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was then added to ice water (50 mL) and the formed solid was filtered, washed with water (20 mL) and dried at 40 ° C. under high vacuum. This gave 807 mg (92% of theory) of the target compound, which was converted without further purification.

LC-MS (Method 1): Rt = 0.70 min; MS (ESI cation): m / z = 226 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.38 (s, 3H), 3.40 (s, 3H), 7.52 (d, 1H), 7.99 (d, 1H).

Example 19A
5-Amino-6-fluoro-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one

  First, 806 mg (3.58 mmol) of 5-fluoro-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzimidazol-2-one from Example 18A was added to a THF / methanol mixture (1 2) Put in 22.2 mL, then add 38 mg (0.04 mmol) of palladium (10% activated carbon supported product) and hydrogenate the mixture at standard hydrogen pressure overnight. The reaction mixture was then filtered through diatomaceous earth, the residue was washed with methanol, the filtrate was concentrated and dried under high vacuum. This gave 668 mg (85% purity, 81% of theory) of the target compound, which was converted without further purification.

LC-MS (Method 1): Rt = 0.43 min; MS (ESI cation): m / z = 196 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.21 (s, 3H), 3.22 (s, 3H), 4.78 (br.s, 2H), 6.53 ( d, 1H), 6.98 (d, 1H).

Example 20A
5-Amino-3-hydroxy-1-methyl-3- (trifluoromethyl) -1,3-dihydro-2H-indol-2-one

  First, 3-hydroxy-1-methyl-5-nitro-3- (trifluoromethyl) -1,3-dihydro-2H-indol-2-one [for the production of Journal of Heterocyclic Chemistry, 2008, 45, 4, p. 969-973] 2.45 g (8.87 mmol) was placed in 20.0 mL of ethanol, then 600 mg of palladium (10% activated carbon support) was added and the mixture was hydrogenated at standard hydrogen pressure for 4 hours. The reaction mixture was then filtered through diatomaceous earth, the residue was washed with methanol (30 mL), and the filtrate was concentrated. This gave 2.06 g (91% of theory) of the target compound.

LC-MS (Method 2): Rt = 0.97 min; MS (ESI cation): m / z = 247 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.07 (s, 3H), 4.97-5.33 (m, 2H), 6.64 (dd, 1H), 6. 77-6.81 (m, 2H), 7.51 (s, 1H).

Example 21A
Ethyl 2,4-dioxo-3- [4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemic body)

  5.2 g (20 mmol) of 1- [4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] urea from Example 13A and 8.26 mL (41 mmol) of diethyl (ethoxymethylene) malonate ) Was heated to reflux at 140 ° C. for 24 hours (although it was hardly stirred at the start, it became homogeneous and could be stirred thereafter). After cooling to room temperature, 47.7 mL of ethanol and 2.78 g (41 mmol) of sodium ethoxide were added and the mixture was heated to reflux for an additional 24 hours. For workup, the reaction mixture was concentrated under reduced pressure, acidified with 1M hydrochloric acid (80 mL), and extracted three times with ethyl acetate at 80 mL each time. The combined organic phases were dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was chromatographed on silica gel (petroleum ether / ethyl acetate 3: 1 to 1: 3). This gave 4.20 g (56% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.94 min; MS (ESI cation): m / z = 369 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 2.27-2.38 (m, 1H), 2.39-2.49 (m, 1H) ), 3.01-3.13 (m, 1H), 3.23-3.32 (m, 1H), 4.10-4.22 (m, 2H), 6.29-6.46 (m) 1H), 7.29-7.39 (m, 2H), 7.52 (d, 1H), 8.13-8.20 (m, 1H), 11.74-11.99 (m, 1H) ).

Example 22A
1- (1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl

  First, 1.00 g (4.13 mmol) of 5-amino-1,3-diethyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride, 0.63 mL (4.55 mmol) of triethylamine and 3- Ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate (for production see Senda, Shigeo; Hirota, Kosaku; Notani, Jyoji, Chemical & Pharmaceutical Bulletin (1972), 20 (7), 1380). 1.07 g (4.13 mmol) was placed in 31 mL of ethanol and the mixture was heated to reflux for 2 hours. Next, 464 mg (4.13 mmol) of potassium tert-butoxide was added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then heated to reflux for an additional 3 hours. For workup, water was added at room temperature and the mixture was acidified with 1N hydrochloric acid. The precipitated solid was filtered off with suction, washed once with water and ethyl acetate, and dried in vacuo at 50 ° C. This gave 783 mg (51% of theory) of the target compound.

LC-MS (Method 3): Rt = 0.84 min; MS (ESI cation): m / z = 373 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.18-1.26 (m, 9H), 3.83-3.95 (m, 4H), 4.17 (q, 2H) ), 7.18 (dd, 1H), 7.31 (d, 1H), 7.44 (d, 1H), 8.30 (s, 1H), 11.68 (s, 1H).

Example 23A
1-methyl-5-nitro-3- (2,2,2-trifluoroethyl) -1,3-dihydro-2H-benzimidazol-2-one

  1-Methyl-5-nitro-1,3-dihydro-2H-benzimidazol-2-one [synthesis as described in US 6,114,532] 8.00 g (41.4 mmol) was first added to 11.45 g potassium carbonate. (82.8 mmol) was added to 600 mL of acetonitrile / DMF 2: 1 (volume ratio), and 7.48 mL (45.6 mmol) of 2,2,2-trifluoroethyl trichloromethanesulfonate was added. The reaction mixture was heated to reflux temperature and stirred at this temperature overnight. After cooling to room temperature, the mixture was poured into 1.8 liters of 0.1N hydrochloric acid. The precipitated solid was filtered and dried under HV. This gave 11.3 g (97% of theory) of the title compound.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.44 (s, 3H), 4.97 (q, 2H), 7.44 (d, 1H), 8.14 (dd, 1H), 8.33 (d, 1H).

Example 24A
5-Amino-1-methyl-3- (2,2,2-trifluoroethyl) -1,3-dihydro-2H-benzimidazol-2-one

  Initially, 11.3 g (41.06 mmol) of the compound from Example 23A was placed in 623 mL of methanol / tetrahydrofuran 2: 1 (volume ratio). 1.66 g palladium / carbon (10% on carbon) and 25.9 g (410.6 mmol) ammonium formate were added and the reaction mixture was stirred at 70 ° C. for 4 hours. After cooling to room temperature, the catalyst was filtered and the solvent was removed from the filtrate with a rotary evaporator. The residue was mixed with 100 mL saturated sodium bicarbonate solution and 400 mL water. The formed solid was filtered, washed with 50 mL of water and dried under HV. This gave 8.90 g (86% of theory) of the title compound.

LC-MS (Method 5): Rt = 0.41 min; m / z = 246 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.25 (s, 3H), 4.63 (q, 2H), 4.89 (br.s, 2H), 6.37 ( dd, 1H), 6.48 (s, 1H), 6.85 (d, 1H).

Example 25A
1- [1-Methyl-2-oxo-3- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-benzimidazol-5-yl] -2,4-dioxo-1,2 , 3,4-Tetrahydropyrimidine-5-carboxylate

  8.90 g (36.3 mmol) of the compound from Example 24A and ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate (for preparation, Senda, Shigeo; Hirota, Kosaku; Notani, Jyoji, Chemical & (See Pharmaceutical Bulletin (1972), 20 (7), 1380-8). 9.41 g (36.3 mmol) was heated in 784 mL of ethanol and allowed to reflux for 1.5 hours. After cooling slightly (about 60 ° C.), 4.07 g (36.3 mmol) of potassium tert-butoxide was added. The reaction mixture was heated again to reflux temperature for 30 minutes. After cooling to room temperature, the reaction mixture was poured into 5 liters of ice-cold 1N hydrochloric acid. The precipitated solid was filtered, washed with 800 mL of water and dried under HV. This gave 12.7 g (83% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.70 min; m / z = 413 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 3.40 (s, 3H), 4.17 (q, 2H), 4.78 (q, 2H), 7.25-7.30 (m, 1H), 7.31-7.36 (m, 1H), 7.52 (s, 1H), 8.26 (s, 1H), 11.71 (S, 1H).

Example 26A
2,4-Dioxo-1- (2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  1.00 g (6.71 mmol) of 5-amino-1,3-dihydro-2H-benzimidazol-2-one and 1.74 g (6.71 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate ) Was used to prepare the target compound as in Example 25A. This gave 1.60 g (75% of theory) of the target compound.

LC-MS (Method 1): Rt = 0.46 min; MS (ESI cation): m / z = 317 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 4.16 (q, 2H), 6.97-7.04 (m, 2H), 7. 07-7.10 (m, 1H), 8.23 (s, 1H), 10.84-10.90 (m, 2H), 11.61 (s, 1H).

Example 27A
1- (6-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  3-Ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate (for production, Senda, Shigeo; Hirota, Kosaku; Notani, Jyoji, Chemical & Pharmaceutical Bulletin (1972), 20 (7), 80 (8), 80 Reference) 1.59 g (6.13 mmol) and 1.00 g (6.13 mmol) of 5-amino-6-methyl-1,3-dihydro-2H-benzimidazol-2-one in 46 mL of ethanol for 2 hours Heated to reflux. Thereafter, 0.69 g (6.13 mmol) of potassium tert-butoxide was added at room temperature, and the reaction mixture was stirred at room temperature overnight and refluxed for 1 hour. For workup, the reaction mixture was mixed with water and acidified with 1N hydrochloric acid. The formed solid was filtered, washed with water and ethyl acetate and dried in vacuo at 50 ° C. This gave 1.46 g (72% of theory) of the target compound.

LC-MS (Method 1): Rt = 0.52 min; MS (ESI cation): m / z = 331 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 2.08 (s, 3H), 4.16 (q, 2H), 6.89 (s, 1H), 7.03 (s, 1H), 8.19 (s, 1H), 10.77 (s, 1H), 10.78 (s, 1H), 11.65 (s, 1H).

Example 28A
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl

  First, 40.0 g (243.7 mmol) of 6-amino-3-methyl-1,3-benzoxazol-2 (3H) -one was placed in 2.5 liters of ethanol, and 3-ethoxy-2-[(( Ethoxycarbonyl) carbamoyl] ethyl acrylate (for production see Senda, Shigeo; Hirota, Kosaku; Notani, Jioji, Chemical & Pharmaceutical Bulletin (1972), 20 (7), 1380-2g. 1380-8g). 7 mmol) was added. After a few minutes, a thick suspension formed. The mixture was heated to reflux temperature for 1.5 hours. After cooling slightly (about 60 ° C.), 27.3 g (243.7 mmol) of potassium tert-butoxide was added, and the reaction mixture was further stirred at reflux temperature for 4.5 hours. For workup, the reaction suspension was cooled slightly (about 60 ° C.) and placed in about 10 liters of cold 1N hydrochloric acid with stirring. The solid was filtered off with suction, washed with water and dried in a vacuum drying cabinet at 70 ° C. overnight. This gave 64.0 g (79% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.59 min; MS (ESI cation): m / z = 332 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 3.38 (s, 3H), 4.17 (q, 2H), 7.38 (s, 2H), 7.59 (s, 1H), 8.26 (s, 1H), 11.69 (s, 1H).

Example 29A
6-Amino-3-ethyl-1,3-benzoxazol-2 (3H) -one

  First, 3-ethyl-6-nitro-1,3-benzoxazol-2 (3H) -one [for production see WO2007 / 120339A1, 37-38] 1.00 g (4.80 mmol) in ethanol To 32.5 mL, 51 mg (0.05 mmol) of palladium (10% activated carbon supported product) was added, and the mixture was hydrogenated at standard hydrogen pressure overnight. The reaction mixture was then filtered through diatomaceous earth and the filtrate was concentrated. The residue was taken up in 50.0 mL of an ethanol / THF mixture (1: 1), 50 mg (0.05 mmol) of palladium (10% activated carbon support) was added, and the mixture was further hydrogenated at standard hydrogen pressure overnight. The reaction mixture was filtered again through diatomaceous earth, the filter cake was washed with ethanol and the filtrate was concentrated. The residue was extracted and stirred in ethanol, and the solid was filtered and washed with ethanol. After drying under high vacuum, this gave 747 mg (83% of theory) of the target compound.

LC-MS (Method 3): Rt = 0.29 min; MS (ESI cation): m / z = 179 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.21 (t, 3H), 3.74 (q, 2H), 4.99-5.05 (m, 2H), 6. 42 (dd, 1H), 6.55 (d, 1H), 6.94 (d, 1H).

Example 30A
1- (3-Ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl

  First, 746 mg (4.19 mmol) of 6-amino-3-ethyl-1,3-benzoxazol-2 (3H) -one from Example 29A and 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylic 1.09 g (4.19 mmol) of ethyl acid was placed in 32 mL of ethanol, and the mixture was heated to reflux for 2 hours. After cooling to room temperature, 470 mg (4.19 mmol) of potassium tert-butoxide was added and the reaction mixture was further stirred at room temperature overnight. The mixture was then heated to reflux for 1 hour. For workup, the reaction mixture was mixed with water at room temperature and acidified with 1M hydrochloric acid. The formed solid was filtered, washed with water and ethyl acetate / MTBE (1: 1) and dried at 50 ° C. under reduced pressure overnight. This gave 951 mg (66% of theory) of the target compound.

LC-MS (Method 1): Rt = 0.71 min; MS (ESI cation): m / z = 346 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 1.28 (t, 3H), 3.90 (q, 2H), 4.17 (q, 2H), 7.36-7.41 (m, 1H), 7.43-7.47 (m, 1H), 7.59-7.62 (m, 1H), 8.28 (s, 1H) 11.70 (s, 1H).

Example 31A
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl

  First, 6-amino-3-methyl-1,3-benzothiazol-2 (3H) -one (J. Het. Chem. 1992, 29 (5), 1069-1076, Example 8b) 450 mg (2. 50 mmol) and 647 mg (2.50 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate were placed in 19 mL of ethanol and the mixture was heated to reflux for 2 hours. After cooling to room temperature, 280 mg (2.50 mmol) of potassium tert-butoxide was added and the reaction mixture was further stirred at room temperature overnight. For workup, the reaction mixture was diluted with water, acidified with 1M hydrochloric acid, and the solid formed was filtered. The solid was washed with water and ethyl acetate and dried in vacuo at 50 ° C. overnight. This gave 736 mg (85% of theory) of the target compound.

LC-MS (Method 1): Rt = 0.70 min; MS (ESI cation): m / z = 348 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 3.45 (s, 3H), 4.17 (q, 2H), 7.42-7. 47 (m, 1H), 7.51-7.55 (m, 1H), 7.83-7.86 (m, 1H), 8.32 (s, 1H), 11.71 (s, 1H) .

Example 32A
1-methyl-6-nitro-1,3-dihydro-2H-benzimidazol-2-one

First, 500 mg (2.99 mmol) of N ² -methyl-4-nitrobenzene-1,2-diamine [Synthesis described in WO2008 / 128009, page 49] is placed in DMF (9 mL), followed by 4.17 mL of triethylamine. (0.73 mmol) and 2.42 g (15.0 mmol) of N, N′-carbonyldiimidazole were added and the mixture was stirred at 100 ° C. for 5 hours. The reaction mixture was then mixed with water and adjusted to pH 3 with 1M hydrochloric acid. The formed solid was filtered, washed with water and dried at 50 ° C. under reduced pressure overnight. This gave 482 mg (purity 91%, 76% of theory) of the target compound. The crude product was converted without further purification.

LC-MS (Method 3): Rt = 0.71 min; MS (ESI cation): m / z = 194 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.37 (s, 3H), 7.15 (d, 1H), 7.97-8.01 (m, 1H), 8. 02-8.03 (m, 1H), 11.64 (s, 1H).

Example 33A
6-amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

  First, 480 mg (2.49 mmol) of the nitro compound from Example 32A was placed in 31 mL of ethanol, then 132 mg (0.12 mmol) of palladium (10% activated carbon support) was added, and the mixture was stirred at standard hydrogen pressure for 2 hours. Hydrogenated. The reaction mixture was then filtered through diatomaceous earth, the residue was washed with methanol, and the filtrate was concentrated. This gave 418 mg (purity 90%, 93% of theory) of the target compound. The crude product was converted without further purification.

LC-MS (Method 2): Rt = 0.27 min; MS (ESI cation): m / z = 164 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.16 (s, 3H), 4.72 (s, 2H), 6.23 (dd, 1H), 6.28-6. 31 (m, 1H), 6.63 (d, 1H), 10.28 (s, 1H).

Example 34A
1- (3-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  First, 410 mg (2.51 mmol) of 6-amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one from Example 33A and (2E) -3-ethoxy-2-[(ethoxy Carbonyl) carbamoyl] ethyl acrylate [For production, see Senda, Shigeo; Hirota, Kosaku; Notani, Jioji, Chemical & Pharmaceutical Bulletin (1972), 20 (7), 1380-1388 (1380-1388). In ethanol (19 mL) and the mixture was heated to reflux for 2 hours. Next, 282 mg (2.51 mmol) of potassium tert-butoxide was added at room temperature, and the mixture was further heated to reflux for 3 hours. For workup, the reaction mixture was mixed with water and acidified to pH 3 with 1N hydrochloric acid. The formed solid was filtered off with suction, washed with ethyl acetate and dried in vacuo at 50 ° C. This gave 251 mg (purity 73%, 22% of theory) of the target compound, which was converted without further purification. The remaining filtrate was extracted three times with ethyl acetate and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was extracted and stirred in an ethyl acetate / MTBE mixture and the solid was filtered and dried under high vacuum. This gave an additional 443 mg (53% of theory) of the target compound.

LC-MS (Method 1): Rt = 0.51 min; MS (ESI cation): m / z = 331 (M + H) ⁺ .

Example 35A
5-Amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

  First, 29.5 g (150 mmol) of 1-methyl-5-nitro-1,3-dihydro-2H-benzimidazol-2-one [synthesis described in US Pat. No. 6,114,532] was placed in 630 mL of methanol and 315 mL of THF. , 1.62 g of palladium (10% activated carbon supported product) was added, and the mixture was hydrogenated at room temperature under atmospheric hydrogen. After completion of the reaction, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated using a rotary evaporator. The residue was stirred with diethyl ether, filtered off with suction and dried. This gave 24.5 g (96% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.16 min; MS (ESI cation): m / z = 164 (M + H) ⁺ .

Example 36A
1- (1-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  5.00 g (29.3 mmol) of 5-amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one and 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylic from Example 35A 7.60 g (29.3 mmol) of ethyl acid was heated to reflux in 250 mL of ethanol for 2 hours. After cooling to room temperature, 3.29 g (29.3 mmol) of potassium tert-butoxide was added and the reaction mixture was heated to reflux for an additional 2.5 hours. For workup, the reaction mixture was acidified with 4M hydrochloric acid at room temperature and diluted with water. The mixture was partially concentrated under reduced pressure and the remaining suspension was filtered. The filter residue was washed with water and ethyl acetate and dried in vacuo at 30 ° C. This gave 7.56 g (78% of theory) of the target compound.

LC-MS (Method 5): Rt = 0.52 min; MS (ESI cation): m / z = 331 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 3.31 (s, 3H), 4.16 (q, 2H), 7.10-7. 21 (m, 3H), 8.23 (s, 1H), 11.12 (s, 1H), 11.63 (s, 1H).

Example 37A
N- [4- (Cyclobutylamino) -3-nitrophenyl] acetamide

  First, 1.00 g (5.04 mmol) of N- (4-fluoro-3-nitrophenyl) acetamide (for production see WO2005 / 72741, page 26, Example 117A) and 0.86 mL of cyclobutylamine (10 .09 mmol) in 40 mL of ethanol, then 1.40 mL (10.09 mmol) of triethylamine was added and the reaction mixture was stirred in a microwave apparatus at 140 ° C. for 1.5 hours. For workup, the mixture was concentrated under reduced pressure, the residue was stirred with MTBE, the solid formed was filtered and dried under high vacuum. This gave 185 mg (purity 69%, 10% of theory) of the target compound. The remaining filtrate was concentrated and the residue was taken up in ethyl acetate, washed once each with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. After drying under high vacuum, this gave an additional 1.01 g (78% of theory) of the target compound.

LC-MS (Method 3): Rt = 1.31 min; MS (ESI cation): m / z = 250 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.70-1.85 (m, 2H), 1.93-2.04 (m, 5H), 2.39-2.47 (M, 2H), 4.12 (sxt, 1H), 6.92 (d, 1H), 7.65 (dd, 1H), 7.93 (d, 1H), 8.46 (d, 1H) , 9.97 (s, 1H).

Example 38A
N- [3-amino-4- (cyclobutylamino) phenyl] acetamide

  First, 1.02 g (4.07 mmol) of N- [4- (cyclobutylamino) -3-nitrophenyl] acetamide from Example 37A was placed in 96 mL of ethyl acetate and then palladium (10% activated carbon supported product). ) 216 mg (0.20 mmol) was added and the mixture was hydrogenated at standard hydrogen pressure for 2 hours. The reaction mixture was then filtered through diatomaceous earth, the residue was washed with methanol, and the filtrate was concentrated. This gave 870 mg (purity 90%, 87% of theory) of the title compound. The crude product was converted without further purification.

LC-MS (Method 2): Rt = 1.01 min; MS (ESI cation): m / z = 220 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.64-1.87 (m, 4H), 1.93 (s, 3H), 2.28-2.38 (m, 2H) ), 3.76 (sxt, 1H), 4.42 (d, 1H), 4.51-4.60 (m, 2H), 6.20 (d, 1H), 6.61 (dd, 1H) 6.82 (d, 1H), 9.34 (s, 1H).

Example 39A
N- (1-cyclobutyl-1H-benzimidazol-5-yl) acetamide

  First, 870 mg (3.96 mmol) of N- [3-amino-4- (cyclobutylamino) phenyl] acetamide from Example 38A is placed in 25 mL of (diethoxymethoxy) ethane and then 0.43 mL of concentrated hydrochloric acid. (5.17 mmol) was added dropwise and the reaction mixture was stirred at room temperature overnight. The precipitated solid was filtered off with suction, washed with ethyl acetate and dried under high vacuum. This gave 930 mg (100% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.43 min; MS (ESI cation): m / z = 230 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.89-2.00 (m, 2H), 2.11 (s, 3H), 2.57-2.64 (m, 4H) ), 5.15 (5-wire, 1H), 7.59-7.64 (m, 1H), 7.86 (d, 1H), 8.38 (d, 1H), 9.66 (s, 1H), 10.53 (s, 1H).

Example 40A
1-cyclobutyl-1H-benzimidazol-5-amine

  First, 920 mg (4.01 mmol) of N- (1-cyclobutyl-1H-benzimidazol-5-yl) acetamide from Example 39A was placed in 20 mL of a 1: 1 mixture of 1M hydrochloric acid and ethanol and the reaction mixture was added to 120 mL. Stir for 1 hour at ° C. The reaction mixture is cooled to room temperature, concentrated, taken up in ethyl acetate and washed once each with 1N sodium hydroxide solution and saturated sodium chloride solution, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. did. This gave 593 mg (75% of theory) of the title compound.

LC-MS (Method 2): Rt = 0.89 min; MS (ESI cation): m / z = 189 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.80-1.92 (m, 2H), 2.43-2.48 (m, partially hidden by DMSO signal ), 4.66-4.76 (m, 2H), 4.82 (5-fold, 1H), 6.59 (dd, 1H), 6.76 (d, 1H), 7.24 (d, 1H), 8.07 (s, 1H).

Example 41A
Ethyl 1- (1-cyclobutyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The target compound was produced and purified in the same manner as in Example 27A, with the reaction time being 3 hours under reflux. Starting from 590 mg (3.15 mmol) 1-cyclobutyl-1H-benzimidazol-5-amine and 817 mg (3.15 mmol) ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate from Example 40A. 832 mg (67% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.62 min; MS (ESI cation): m / z = 355 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.18 (t, 3H), 1.86-1.97 (m, 2H), 2.55 to 2.58 (m, part) 3.40-3.48 (m, 1H), 4.06 (q, 2H), 5.01 (5-fold, 1H), 7.16 (dd, 1H), 7.54 (d, 1H), 7.62 (d, 1H), 7.96 (s, 1H), 8.45 (s, 1H).

Example 42A
N-ethyl-2,4-dinitroaniline

  First, 2.00 g (9.87 mmol) of 1-chloro-2,4-dinitrobenzene is placed in 20 mL of THF, and then 5.92 mL (11.84 mmol) of a solution of 2M ethylamine in THF is added dropwise at 0 ° C. The reaction mixture was stirred at room temperature overnight. Then, at 0 ° C., an additional 9.86 mL (19.73 mmol) of 2M ethylamine in THF was added and the reaction was stirred at room temperature for an additional 5 hours. Next, at 0 ° C., an additional 4.93 mL (9.86 mmol) of a 2M ethylamine solution in THF was added and stirring was continued overnight. For workup, the reaction mixture was mixed with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The obtained residue was subjected to extraction stirring in MTBE, and the precipitated solid was subjected to suction filtration. The filtrate was concentrated to give the title compound in a total yield of 2.29 g (100% of theory).

LC-MS (Method 1): Rt = 0.97 min; MS (ESI cation): m / z = 212 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.49-3.58 (m, 2H), 7.23 (d, 1H), 8. 26 (dd, 1H), 8.81-8.89 (m, 2H).

Example 43A
N ¹ -ethyl-4-nitrobenzene-1,2-diamine

  First, 1.20 g (5.68 mmol) of N-ethyl-2,4-dinitroaniline from Example 42A was placed in 3 mL of acetonitrile under argon, and 64 mg (0.06 mmol) of palladium (10% activated carbon support). And 3.40 mL (24.38 mmol) of triethylamine were added. The reaction mixture was cooled to −15 ° C. and a solution of 1.03 mL (27.44 mmol) formic acid in acetonitrile (3 mL) was added. The reaction mixture was stirred at 40 ° C. for 1 hour and 60 ° C. for 2 hours. For workup, the reaction mixture was filtered through diatomaceous earth at room temperature, washed with ethyl acetate / methanol (1: 1) and the filtrate was concentrated. The residue was mixed with water and the precipitated solid was filtered off with suction, washed with water and dried at 50 ° C. under reduced pressure. This gave 546 mg (47% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.79 min; MS (ESI cation): m / z = 182 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.18-3.26 (m, 2H), 5.09-5.20 (m, 2H) ), 5.87 (t, 1H), 6.46 (d, 1H), 7.39 (d, 2H), 7.52 (dd, 1H).

Example 44A
1-ethyl-5-nitro-1H-benzimidazole

First, 540 mg (2.98 mmol) of N ¹ -ethyl-4-nitrobenzene-1,2-diamine from Example 43A is placed in 19 mL of (diethoxymethoxy) ethane and then 0.32 mL of concentrated hydrochloric acid (3. 89 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure and the residue was extracted and stirred in MTBE, filtered, washed with MTBE and dried. This gave 486 mg (54% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.65 min; MS (ESI cation): m / z = 192 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.46 (t, 3H), 4.42 (q, 2H), 7.97 (d, 1H), 8.26 (d, 1H), 8.60 (d, 1H), 8.83-8.90 (m, 1H).

Example 45A
1-ethyl-1H-benzimidazol-5-amine

  The target compound was produced and purified in the same manner as in Example 33A, and the reaction was performed overnight. Starting from 485 mg (2.53 mmol) of 1-ethyl-5-nitro-1H-benzimidazole from Example 44A, 417 mg (101% of theory) of the title compound were obtained.

LC-MS (Method 2): Rt = 0.23 min; MS (ESI cation): m / z = 162 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.47 (t, 3H), 4.36 (q, 2H), 6.85-6.96 (m, 2H), 7. 64 (d, 1H), 9.16 (s, 1H).

Example 46A
Ethyl 1- (1-ethyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  First, 659 mg (2.54 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate and 410 mg (2.54 mmol) of 1-ethyl-1H-benzimidazol-5-amine from Example 45A. Into 19 mL of ethanol, the mixture was stirred at reflux for 2 hours. Thereafter, 285 mg (2.54 mmol) of potassium tert-butoxide was added at room temperature, and the reaction mixture was heated to reflux for 3 hours. For workup, the reaction mixture was mixed with water and the mixture was concentrated under reduced pressure. The residue was stirred with dichloromethane / methanol, filtered and the filtrate was concentrated. The residue thus obtained was stirred in MTBE / ethyl acetate and the solid was filtered, washed with ethyl acetate and then dried at 50 ° C. under reduced pressure. This gave 491 mg (59% of theory) of the title compound.

LC-MS (Method 3): Rt = 0.60 min; MS (ESI cation): m / z = 329 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.7-1.23 (m, 3H), 1.42 (t, 3H), 4.08-4.16 (m, 2H) ), 4.28-4.36 (m, 2H), 7.26 (d, 1H), 7.63-7.71 (m, 2H), 8.15 (s, 1H), 8.35 ( s, 1H).

Example 47A
N-isopropyl-2,4-dinitroaniline

  First, 1.00 g (4.93 mmol) of 1-chloro-2,4-dinitrobenzene is placed in 10 mL of THF, then 0.84 mL (9.87 mmol) of isopropylamine is added dropwise, and the reaction mixture is stirred at room temperature for 16 hours. Stir. For workup, the mixture was mixed with saturated sodium bicarbonate solution and washed three times with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. This gave 1.13 g (99% of theory) of the title compound.

LC-MS (Method 3): Rt = 1.30 min; MS (ESI cation): m / z = 226 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.31 (d, 6H), 4.02-4.15 (m, 1H), 7.27 (d, 1H), 8. 27 (dd, 1H), 8.42 (d, 1H), 8.86 (d, 1H).

Example 48A
N ¹ -Isopropyl-4-nitrobenzene-1,2-diamine

  The reaction time was 7 hours, and the target compound was produced and purified in the same manner as in Example 43A. Starting from 1.13 g (5.01 mmol) of N-isopropyl-2,4-dinitroaniline from Example 47A, 708 mg (72% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.88 min; MS (ESI cation): m / z = 196 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.21 (d, 6H), 3.69-3.81 (m, 1H), 5.11-5.24 (m, 2H) ), 5.62 (d, 1H), 6.49 (d, 1H), 7.39 (d, 1H), 7.51 (dd, 1H).

Example 49A
1-isopropyl-5-nitro-1H-benzimidazole

Using N ¹ -isopropyl-4-nitrobenzene-1,2-diamine 700 mg (3.58 mmol) from Example 48A and 23 mL (137.49 mmol) (diethoxymethoxy) ethane in the same manner as Example 39A, the target The compound was manufactured. For workup, the mixture was concentrated and the residue was stirred with MTBE, filtered and dried under high vacuum. This gave 760 mg of the title compound. The crude product was converted without further purification.

LC-MS (Method 3): Rt = 0.98 min; MS (ESI cation): m / z = 206 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.58 (d, 6H), 4.88-4.99 (m, 1H), 8.01 (d, 1H), 8. 24 (dd, 1H), 8.60 (d, 1H), 8.94-9.01 (m, 1H).

Example 50A
1-isopropyl-1H-benzimidazol-5-amine

  The reaction time was 16 hours, and the target compound was produced and purified in the same manner as in Example 33A. Starting from 750 mg (3.65 mmol) of 1-isopropyl-5-nitro-1H-benzimidazole from Example 49A, 612 mg (95% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.23 min; MS (ESI cation): m / z = 176 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.56 (d, 6H), 3.34 (s, hidden by water signal), 4.77-4.90 (m 1H), 6.87-6.95 (m, 2H), 7.67 (d, 1H), 9.22 (s, 1H).

Example 51A
1- (1-Isopropyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  In the same manner as in Example 27A, the target compound was produced and purified. Starting from 612 mg (3.49 mmol) of 1-isopropyl-1H-benzimidazol-5-amine from Example 50A and 905 mg (3.49 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate. 684 mg (57% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.56 min; MS (ESI cation): m / z = 343 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.21 (t, 3H), 1.56 (d, 6H), 4.15 (q, 2H), 4.81 (spt, 1H), 7.32 (d, 1H), 7.71-7.79 (m, 2H), 8.26 (s, 1H), 8.47 (s, 1H), 11.66 (br.s) 1H).

Example 52A
N- {4-[(cyclopropylmethyl) amino] -3-nitrophenyl} acetamide

  The target compound was produced and purified in the same manner as in Example 37A. Starting from 1.00 g (5.04 mmol) of N- (4-fluoro-3-nitrophenyl) acetamide and 1.04 mL (10.09 mmol) of cyclopropylmethylamine, 1.34 g of the title compound was obtained. The crude product was converted without further purification.

LC-MS (Method 3): Rt = 1.10 min; MS (ESI cation): m / z = 250 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.27-0.33 (m, 2H), 0.49-0.55 (m, 2H), 1.10-1.22 (M, 1H), 2.02 (s, 3H), 3.21 (t, 2H), 7.07 (d, 1H), 7.65 (dd, 1H), 8.09 (t, 1H) 8.46 (d, 1H), 9.96 (s, 1H).

Example 53A
N- {3-amino-4-[(cyclopropylmethyl) amino] phenyl} acetamide

  In the same manner as in Example 38A, the target compound was produced and purified. Starting from 1.10 g (4.41 mmol) of N- {4-[(cyclopropylmethyl) amino] -3-nitrophenyl} acetamide from Example 52A, 952 mg (98% of theory) of the title compound are obtained. It was.

LC-MS (Method 2): Rt = 0.92 min; MS (ESI cation): m / z = 220 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.17-0.23 (m, 2H), 0.42-0.52 (m, 2H), 1.01-1.13 (M, 1H), 1.93 (s, 3H), 2.83 (t, 2H), 4.22 (t, 1H), 4.50-4.65 (m, 2H), 6.31 ( d, 1H), 6.64 (dd, 1H), 6.84 (d, 1H), 9.36 (s, 1H).

Example 54A
N- [1- (Cyclopropylmethyl) -1H-benzimidazol-5-yl] acetamide

  The target compound was produced and purified in the same manner as Example 39A. Starting from 951 mg (4.33 mmol) N- {3-amino-4-[(cyclopropylmethyl) amino] phenyl} acetamide from Example 53A and 28 mL (166.29 mmol) (diethoxymethoxy) ethane, the title 929 mg (84% of theory) of compound were obtained.

LC-MS (Method 3): Rt = 0.39 min; MS (ESI cation): m / z = 230 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.47−0.53 (m, 2H), 0.58−0.64 (m, 2H), 1.32-1.43 (M, 1H), 2.10 (s, 3H), 4.25 (d, 2H), 7.55 (dd, 1H), 7.87 (d, 1H), 8.30 (d, 1H) , 9.22 (s, 1H), 10.34 (s, 1H).

Example 55A
1- (Cyclopropylmethyl) -1H-benzimidazol-5-amine

  In the same manner as in Example 40A, the target compound was produced and purified. Starting from 828 mg (3.61 mmol) of N- [1- (cyclopropylmethyl) -1H-benzimidazol-5-yl] acetamide from Example 54A, 482 mg (70% of theory) of the title compound were obtained. .

LC-MS (Method 2): Rt = 0.87 min; MS (ESI cation): m / z = 188 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.34-0.40 (m, 2H), 0.48-0.55 (m, 2H), 1.19-1.30. (M, 1H), 3.96 (d, 2H), 4.71 (br.s, 2H), 6.59 (dd, 1H), 6.77 (d, 1H), 7.27 (d, 1H), 7.97 (s, 1H).

Example 56A
1- [1- (Cyclopropylmethyl) -1H-benzimidazol-5-yl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  547 mg (2.92 mmol) of 1- (cyclopropylmethyl) -1H-benzimidazol-5-amine from Example 55A and 757 mg (2.92 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate The reaction time was 5 hours, and the target compound was produced in the same manner as in Example 31A. For workup, the reaction mixture was concentrated, the residue was extracted and stirred in ethyl acetate / methanol, the solid was suction filtered and dried under high vacuum. This gave 1.02 g (98% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.61 min; MS (ESI cation): m / z = 355 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.41-0.46 (m, 2H), 0.51-0.58 (m, 2H), 1.18 (t, 3H ), 1.25-1.37 (m, 1H), 4.06 (q, 2H), 4.15 (d, 2H), 7.18 (dd, 1H), 7.53 (d, 1H) 7.67 (d, 1H), 7.97 (s, 1H), 8.33 (s, 1H).

Example 57A
1,3,3-trimethyl-5-nitro-1,3-dihydro-2H-indol-2-one

  First, 1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one [For the preparation, see Journal of Organic Chemistry, 2000, vol65, 24, p. 8317-8325] 2.44 g (13.96 mmol) are placed in 12 mL acetic acid, then 0.96 mL (13.96 mmol) nitric acid (65%) is added dropwise at room temperature and the reaction mixture is stirred at room temperature for 2 weeks. did. The reaction mixture was added to ice water and the precipitated solid was filtered off with suction, washed with water and dried at 50 ° C. under reduced pressure. This gave 2.32 g (72% of theory) of the title compound.

LC-MS (Method 5): Rt = 0.89 min; MS (ESI cation): m / z = 221 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.35 (s, 6H), 3.22 (s, 3H), 7.25 (d, 1H), 8.26 (dd, 1H), 8.33 (d, 1H).

Example 58A
5-Amino-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one

  The reaction time was 2 days, and the target compound was produced and purified in the same manner as in Example 33A. Starting from 2.32 g (10.56 mmol) of 1,3,3-trimethyl-5-nitro-1,3-dihydro-2H-indol-2-one from Example 57A, 1.95 g (theoretical) 93% of the amount).

LC-MS (Method 2): Rt = 0.76 min; MS (ESI cation): m / z = 191 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.20 (s, 6H), 3.04 (s, 3H), 4.70-4.80 (m, 2H), 6. 46 (dd, 1H), 6.58 (d, 1H), 6.67 (d, 1H).

Example 59A
2,4-Dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -1,2,3,4-tetrahydropyrimidine-5-carvone Ethyl acid

  In the same manner as in Example 31A, the target compound was produced and purified. 1.95 g (10.26 mmol) of 5-amino-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one from Example 58A and 3-ethoxy-2-[(ethoxycarbonyl) Starting from carbamoyl] ethyl acrylate, 2.84 g (77% of theory) of the title compound 2.66 g (10.26 mmol) were obtained.

LC-MS (Method 2): Rt = 1.62 min; MS (ESI cation): m / z = 358 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 1.29 (s, 6H), 3.17 (s, 3H), 4.17 (q, 2H), 7.13 (d, 1H), 7.40 (dd, 1H), 7.51 (d, 1H), 8.25 (s, 1H), 11.65-11.71 (m, 1H) ).

Example 60A
1'-methylspiro [cyclopropane-1,3'-indole] -2 '(1'H) -one

  First, 5.43 g (135.89 mmol) of sodium hydride (60% in mineral oil) was placed in 40 mL of DMF, and then at 0 ° C., 1-methyl-1,3-dihydro-2H-indole-2- A solution of 5.00 g (33.97 mmol) on in DMF (40 mL) was added dropwise and the reaction mixture was stirred at room temperature for 30 min. Next, 8.81 mL (101.91 mmol) of dibromoethane was added dropwise and the mixture was stirred at room temperature for 1 hour. For workup, the reaction mixture was mixed with water and washed three times with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. This gave 3.78 g (64% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.76 min; MS (ESI cation): m / z = 174 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.48-1.53 (m, 2H), 1.57-1.61 (m, 2H), 3.21 (s, 3H ), 6.97-7.03 (m, 2H), 7.06 (d, 1H), 7.23-7.28 (m, 1H).

Example 61A
1'-methyl-5'-nitrospiro [cyclopropane-1,3'-indole] -2 '(1'H) -one

  First, 3.77 g (21.79 mmol) of 1′-methylspiro [cyclopropane-1,3′-indole] -2 ′ (1′H) -one from Example 60A was placed in 40 mL of glacial acetic acid, followed by Concentrated nitric acid (0.90 mL, 21.79 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. Then additional concentrated nitric acid 0.45 mL (10.89 mmol) was added dropwise and the mixture was stirred at room temperature for an additional 1.5 hours. For workup, the mixture was added to ice water and the precipitated solid was filtered off with suction, washed with water and dried under reduced pressure at 30 ° C. This gave 4.01 g (84% of theory) of the title compound.

GC-MS (Method 6): Rt = 7.21 min; MS (ESI cation): m / z = 219 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.4-1.72 (m, 2H), 1.80-1.99 (m, 2H), 3.3 (s, part Hiding by a water signal), 7.17-7.38 (m, 1H), 7.91-8.09 (m, 1H), 8.14-8.31 (m, 1H).

Example 62A
5'-amino-1'-methylspiro [cyclopropane-1,3'-indole] -2 '(1'H) -one

  First, 1.00 g (4.58 mmol) of 1′-methyl-5′-nitrospiro [cyclopropane-1,3′-indole] -2 ′ (1′H) -one from Example 61A was added to ethyl acetate. In 11 mL, 4.13 g (18.33 mmol) of tin (II) chloride dihydrate was added, and the mixture was heated to reflux for 2.5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and extracted twice with 1N hydrochloric acid. The aqueous phase was adjusted to pH 10 with 1N sodium hydroxide solution and extracted four times with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. This gave 375 mg (42% of theory) of the title compound.

LC-MS (Method 2): Rt = 0.73 min; MS (ESI cation): m / z = 189 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.38-1.46 (m, 4H), 3.11 (s, 3H), 4.65-4.76 (m, 2H ), 6.24 (d, 1H), 6.46 (dd, 1H), 6.73 (d, 1H).

Example 63A
1- (1′-methyl-2′-oxo-1 ′, 2′-dihydrospiro [cyclopropane-1,3′-indole] -5′-yl) -2,4-dioxo-1,2,3 , 4-Tetrahydropyrimidine-5-carboxylate ethyl

  510 mg (1.97 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate and 5'-amino-1'-methylspiro [cyclopropane-1,3'-indole] -2 from Example 62A 370 mg (1.97 mmol) of '(1'H) -one was heated to reflux in 10 mL of ethanol for 45 minutes. Thereafter, 221 mg (1.97 mmol) of potassium tert-butoxide was added at room temperature, and the mixture was stirred at room temperature for 1.5 hours and refluxed for 1 hour. For workup, the reaction mixture was mixed with water and acidified with 1N hydrochloric acid. The formed solid was filtered, washed with water and then dried in vacuo at 30 ° C. This gave 557 mg (78% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.69 min; MS (ESI cation): m / z = 356 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 1.54-1.59 (m, 2H), 1.62-1.68 (m, 2H) ), 3.25 (s, 3H), 4.17 (q, 2H), 7.15-7.20 (m, 2H), 7.35-7.41 (m, 1H), 8.25 ( s, 1H), 11.68 (s, 1H).

Example 64A
2,4-Dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -1,2,3,4-tetrahydropyrimidine-5-carvone Ethyl acid

  First, 388 mg (1.49 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate and 6-amino-1,3,3-trimethyl-1,3-dihydro-2H-indole-2- ON [For manufacturing, see Journal of Medicinal Chemistry, 1989, Vol. 32, (7), 1481-1491] 285 mg (1.49 mmol) was placed in 10 mL of ethanol and the mixture was heated to reflux for 2 hours. Thereafter, 167 mg (1.49 mmol) of potassium tert-butoxide was added at room temperature, and the mixture was stirred at room temperature for 1 hour and under reflux for 15 minutes. For workup, the reaction mixture was mixed with water, acidified with 1N hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was extracted and stirred in MTBE / ethyl acetate, filtered, washed with ethyl acetate, and then dried at 50 ° C. under reduced pressure. The solid precipitated in the filtrate was filtered off with suction and dried in vacuo. This gave a total of 388 mg (68% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.75 min; MS (ESI cation): m / z = 358 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 1.30 (s, 6H), 3.14 (s, 3H), 4.17 (q, 2H), 7.16 (d, 1H), 7.23 (s, 1H), 7.48 (d, 1H), 8.30 (s, 1H), 11.73 (s, 3H).

Example 65A
1- (3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  First, 570 mg (2.20 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate and 6-amino-3,3-dimethyl-1,3-dihydro-2H-indol-2-one [ For production, see US 2006/258589, page 35] 388 mg (2.20 mmol) was placed in 14 mL of ethanol and heated to reflux for 2 hours. Next, at room temperature, 247 mg (2.20 mmol) of potassium tert-butoxide was added, and the mixture was stirred at room temperature for 1 hour and at 60 ° C. for 1 hour. For workup, the reaction mixture was mixed with water, acidified with 1N hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was extracted and stirred in MTBE / ethyl acetate and the solid formed was filtered, washed with ethyl acetate and then dried at 50 ° C. under reduced pressure. This gave 630 mg (79% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.65 min; MS (ESI cation): m / z = 344 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 1.28 (s, 6H), 4.16 (q, 2H), 6.96-7. 01 (m, 1H), 7.04-7.09 (m, 1H), 7.42 (d, 1H), 8.27 (s, 1H), 10.58 (s, 1H), 11.65 (S, 1H).

Example 66A
1- (1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  In the same manner as in Example 31A, the target compound was produced and purified. 1- (6-Amino-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) ethanone [Synthesis described in WO2006 / 12374A1, 2006] 0.81 g (3.96 mmol) and 3- Starting from 1.06 g (3.96 mmol) of ethyl ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate, 626 mg (40% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.84 min; MS (ESI cation): m / z = 372 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 1.34 (s, 6H), 2.18 (s, 3H), 3.93 (s, 2H), 4.16 (q, 2H), 7.13 (dd, 1H), 7.38 (d, 1H), 8.05 (d, 1H), 8.23 (s, 1H), 11. 64 (br.s, 1H).

Example 67A
5-Bromo-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one

  Under argon, 2.64 g (66 mmol) of sodium hydride (60% in mineral oil) was suspended in 25 mL of THF and cooled to 0 ° C. A solution of 4.00 g (18.86 mmol) of 5-bromo-1,3-dihydro-2H-indol-2-one in DMF (25 mL) was added dropwise and the mixture was stirred at 0 ° C. for 30 minutes. Next, 4.11 mL (66 mmol) of methyl iodide was slowly added dropwise thereto, then the reaction mixture was warmed to room temperature and stirring was continued at this temperature overnight. For workup, the mixture was poured onto 200 mL of 1M hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were washed with water and then with a saturated sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dissolved in 200 mL of acetonitrile and the mineral oil was extracted with n-pentane. The removed acetonitrile phase was concentrated on a rotary evaporator and the remaining brownish solid was dried under HV. This gave 4.45 g (84% of theory) of the title compound with a purity of 91%.

LC-MS (Method 3): Rt = 1.18 min; m / z = 254, 256 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.27 (s, 6H), 3.12 (s, 3H), 6.99 (d, 1H), 7.45 (dd, 1H), 7.60 (d, 1H).

Example 68A
1,3,3-trimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3-dihydro-2H-indol-2-one

  3.45 g (about 12.35 mmol) of the compound from Example 67A, 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi-1,3,2 A solution of 4.71 g (18.5 mmol) dioxaborolane (bispinacolatodiboron) and 2.18 g (22.2 mmol) potassium acetate in dioxane (60 mL) was degassed and placed under an argon atmosphere. 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride · dichloromethane complex 1.0 g (1.23 mmol) was added, and the mixture was heated to reflux overnight. After cooling to room temperature, the reaction mixture was filtered through celite, the celite was washed with ethyl acetate, and the entire filtrate was concentrated on a rotary evaporator. The residue was adsorbed on diatomaceous earth in dichloromethane and loaded onto a Biotage silica gel cartridge. The cartridge was eluted with cyclohexane / ethyl acetate. Fractions containing product were concentrated on a rotary evaporator. The residue was stirred with 20 mL of diethyl ether. The solid was filtered, washed with a small amount of diethyl ether and dried under HV. This gave 1.82 g of the title compound. The mother liquor was concentrated, the residue was stirred in pentane and the solid was filtered, yielding an additional 1.13 g of product. Overall yield: 79% of theory.

LC-MS (Method 1): Rt = 1.09 min; m / z = 302 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.27 (s, 6H), 1.29 (s, 12H), 3.14 (s, 3H), 7.03 (d, 1H), 7.58 (br.s, 1H), 7.62 (brd, 1H).

Example 69A
1- [3-Hydroxy-1-methyl-2-oxo-3- (trifluoromethyl) -2,3-dihydro-1H-indol-5-yl] -2,4-dioxo-1,2,3 Ethyl 4-tetrahydropyrimidine-5-carboxylate (racemate)

  1.00 g (4.06 mmol) of 5-amino-3-hydroxy-1-methyl-3- (trifluoromethyl) -1,3-dihydro-2H-indol-2-one from Example 20A and 3-ethoxy 1.05 g (4.06 mmol) of ethyl 2-[(ethoxycarbonyl) carbamoyl] acrylate was refluxed for 1 hour in 100 mL of ethanol. After cooling to room temperature, 0.46 mg (4.06 mmol) of potassium tert-butoxide was added and the reaction mixture was further stirred at room temperature overnight and under reflux for 1 hour. For workup, the reaction mixture was acidified with 1M hydrochloric acid, diluted with water and partially concentrated. The formed solid was filtered, washed with water and dried in vacuo at 40 ° C. overnight. This gave 1.47 g (88% of theory) of the target compound.

LC-MS (Method 1): Rt = 0.72 min; MS (ESI cation): m / z = 414 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (t, 3H), 3.21 (s, 3H), 4.18 (q, 2H), 7.27 (d, 1H), 7.60-7.68 (m, 2H), 7.90 (s, 1H), 8.23 (s, 1H), 11.68 (s, 1H).

Example 70A
3-hydroxy-1,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one (racemic)

  First, under argon, 1-methyl-5-nitro-1H-indole-2,3-dione [for preparation, see Bioorganic & Medicinal Chemistry, 2006, 14 (18), p. 6434-6443] 8.70 g (42.20 mmol) is placed in 200 mL, then 33 mL (46.42 mmol) of 1.4 M magnesium bromide in toluene / THF is added dropwise within 10 minutes at 0 ° C. And the reaction mixture was stirred at room temperature for 16 hours. For workup, the reaction mixture was mixed with cold water and extracted twice with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was separated by preparative HPLC (Method 7). This gave 1.41 g (12% of theory) of the title compound.

LC-MS (Method 5): Rt = 0.63 min; MS (ESI cation): m / z = 223 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.46 (s, 3H), 3.19 (s, 3H), 3.22 (s, 1H), 7.24 (d, 1H), 8.19 (d, 1H), 8.30 (dd, 1H).

Example 71A
5-Amino-3-hydroxy-1,3-dimethyl-1,3-dihydro-2H-indol-2-one (racemic)

  The reaction time was 4 hours, and the target compound was produced and purified in the same manner as in Example 33A. Preparative HPLC (Method) starting from 1.40 g (6.30 mmol) of 3-hydroxy-1,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one from Example 70A After further purification according to 24), 1.15 g (95% of theory) of the title compound were obtained.

LC-MS (Method 2): Rt = 0.48 min; MS (ESI cation): m / z = 193 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.39 (s, 3H), 3.11 (s, 3H), 7.08 (d, 1H), 7.25-7. 32 (m, 2H).

Example 72A
1- (3-hydroxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5 -Ethyl carboxylate (racemate)

  First, 674 mg (2.60 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate and 5-amino-3-hydroxy-1,3-dimethyl-1,3-dihydro from Example 71A -H-indole-2-one 500 mg (2.60 mmol) was placed in 15 mL of ethanol and the mixture was heated to reflux for 1.5 hours. Thereafter, 292 mg (2.60 mmol) of potassium tert-butoxide was added at room temperature, and the reaction mixture was heated to reflux for 10 hours. For workup, the reaction mixture was acidified with 1N hydrochloric acid at room temperature and extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was stirred in MTBE / ethyl acetate and the solid formed was filtered and then dried at 30 ° C. under reduced pressure. The solid precipitated in the filtrate was filtered, washed with water and dried in vacuo. This gave a total of 218 mg (22% of theory) of the title compound.

LC-MS (Method 5): Rt = 0.53 min; MS (ESI cation): m / z = 360 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.41 (s, 3H), 3.14 (s, 3H), 4.18 (q, 2H), 6.10 (s, 1H), 7.11 (d, 1H), 7.43 (d, 1H), 7.52 (s, 1H), 8.20 (s, 1H), 11. 67 (s, 1H).

Example 73A
1- [3-Fluoro-1-methyl-2-oxo-3- (trifluoromethyl) -2,3-dihydro-1H-indol-5-yl] -2,4-dioxo-1,2,3 Ethyl 4-tetrahydropyrimidine-5-carboxylate (racemate)

  First, 1- [3-hydroxy-1-methyl-2-oxo-3- (trifluoromethyl) -2,3-dihydro-1H-indol-5-yl]-from Example 69A under argon. 200 mg (0.48 mmol) of ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate was placed in 4.74 mL of dichloromethane at -78 ° C. Next, 128 μL (0.97 mmol) of diethylaminosulfur trifluoride was added dropwise to bring the mixture to room temperature and further stirred overnight. Thereafter, diethylaminosulfur trifluoride (0.5 eq.) Was added again at −78 ° C. and the mixture was stirred at room temperature for 1 hour. For workup, the mixture was diluted with dichloromethane, washed once with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. This gave 191 mg (91% of theory) of the title compound.

LC-MS (Method 5): Rt = 0.83 min; MS (ESI cation): m / z = 416 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.26 (s, 3H), 4.18 (q, 2H), 7.40 (d, 1H), 7.77-7.83 (m, 1H), 7.91 (s, 1H), 8.34 (s, 1H), 11.72 (s, 1H).

Example 74A
1- (1-Methyl-1H-benzotriazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  317 mg (2.77 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate and 410 mg (2.77 mmol) of 1-methyl-1H-benzotriazol-5-amine [for production, WO 2005/092899, Example 142; see Preparation 265] was heated to reflux in 21 mL of ethanol for 2 hours. Thereafter, 311 mg (2.77 mmol) of potassium tert-butoxide was added at room temperature, and the reaction mixture was further heated to reflux for 3 hours. For workup, the reaction mixture was mixed with water and acidified with 1N hydrochloric acid. The formed solid was filtered, washed with ethyl acetate and dried in vacuo at 50 ° C. This gave 659 mg (76% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.59 min; MS (ESI cation): m / z = 316 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 4.18 (q, 2H), 4.36 (s, 3H), 7.68 (dd, 1H), 7.97 (d, 1H), 8.25-8.29 (m, 1H), 8.40 (s, 1H), 11.75 (s, 1H).

Example 75A
1- (1-Methyl-1H-indazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  1.76 g (6.79 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate and 1.00 g (6.79 mmol) of 1-methyl-1H-indazol-5-amine in 51 mL of ethanol Heated to reflux for hours. Thereafter, 762 mg (6.79 mmol) of potassium tert-butoxide was added at room temperature, and the reaction mixture was further heated to reflux for 3 hours. For workup, the reaction mixture was mixed with water and acidified with 1N hydrochloric acid. The formed solid was filtered, washed with ethyl acetate / MTBE (1: 1) and dried in vacuo at 50 ° C. This gave 1.97 g (92% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.62 min; MS (ESI cation): m / z = 315 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 4.09 (s, 3H), 4.17 (q, 2H), 7.45-7. 52 (m, 1H), 7.75 (d, 1H), 7.91 (s, 1H), 8.15 (s, 1H), 8.32 (s, 1H), 11.68 (s, 1H) ).

Example 76A
1- (1-Methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  1.76 g (6.79 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate in 51 mL of ethanol and 1-methyl-1H-benzimidazol-5-amine [for preparation US2008 / 0090856, See Example B23] 1.00 g (6.79 mmol) was heated to reflux for 2 hours. Thereafter, at room temperature, 0.76 g (6.79 mmol) of potassium tert-butoxide was added, and the reaction mixture was further heated to reflux for 3 hours. For workup, the reaction mixture was mixed with water and acidified with 1N hydrochloric acid. The aqueous phase was concentrated, dichloromethane / methanol (1: 1) was added and the solid formed was filtered. The filtrate was concentrated, MTBE / ethyl acetate (1: 1) was added and the formed solid was filtered, washed with ethyl acetate and then dried at 50 ° C. under reduced pressure. This gave 1.55 g (73% of theory) of the title compound.

LC-MS (Method 2): Rt = 1.00 min; MS (ESI cation): m / z = 315 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 4.03 (s, 3H), 4.18 (q, 2H), 7.62-7. 68 (m, 1H), 7.94-8.00 (m, 1H), 8.00-8.03 (m, 1H), 8.35 (s, 1H), 9.24 (br.s, 1H), 11.73 (s, 1H).

Example 77A
1-methyl-5-nitro-2- (trichloromethyl) -1H-benzimidazole

A suspension of 1.50 g (8.97 mmol) of N ¹ -methyl-4-nitrobenzene-1,2-diamine in glacial acetic acid (40.0 mL) was cooled to 0 ° C. and added to 2,2,2-trichloroacetate. 1.22 mL (9.87 mmol) of methyl imidoate was added dropwise and the mixture was stirred at room temperature for 3 hours. For workup, the mixture was added to water and the solid was filtered and washed with water. The solid was dried at 50 ° C. under high vacuum. This gave 2.50 g (93% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.06 min; MS (ESI cation): m / z = 296 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 4.20 (s, 3H), 8.00 (d, 1H), 8.35 (dd, 1H), 8.75 (d, 1H).

Example 78A
Ethyl 1-methyl-5-nitro-1H-benzimidazole-2-carboxylate

  First, 2.50 g (8.48 mmol) of 1-methyl-5-nitro-2- (trichloromethyl) -1H-benzimidazole from Example 77A was placed in 24.0 mL of ethanol and then silver (I) nitrate. 4.75 g (27.98 mmol) was added and the mixture was heated to reflux overnight. For workup, the mixture was concentrated and the residue was mixed with 1M hydrochloric acid and ethyl acetate. The mixture was then filtered through celite and washed with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The resulting residue was stirred with MTBE and the solid formed was filtered and washed with MTBE. The solid was dried under high vacuum. This gave 0.32 g (15% of theory) of the title compound.

LC-MS (Method 5): Rt = 0.86 min; MS (ESI cation): m / z = 250 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.39 (t, 3H), 4.15 (s, 3H), 4.44 (q, 2H), 7.99 (d, 1H), 8.28-8.35 (m, 1H), 8.69-8.74 (m, 1H).

Example 79A
1-methyl-5-nitro-1H-benzimidazole-2-carboxamide

  First, 745 mg (2.99 mmol) of ethyl 1-methyl-5-nitro-1H-benzimidazole-2-carboxylate from Example 78A was placed in 10.0 mL of THF followed by 27.4 mL of 25% aqueous ammonia ( 54.90 mmol) was added and the mixture was stirred at room temperature for 2.5 hours. For workup, the reaction mixture was mixed with water and the solid formed was filtered, washed with water and dried at 50 ° C. under high vacuum. This gave 512 mg (purity 88%, 68% of theory) of the title compound.

LC-MS (Method 5): Rt = 0.64 min; MS (ESI cation): m / z = 221 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 4.18 (s, 3H), 7.94 (d, 1H), 8.04 (br.s, 1H), 8.28 ( dd, 1H), 8.46 (br.s, 1H), 8.60 (d, 1H).

Example 80A
5-Amino-1-methyl-1H-benzimidazole-2-carboxamide

  First, 512 mg (2.33 mmol) of the nitro compound from Example 79A is placed in 16 mL of ethanol, then 74 mg (0.07 mmol) of palladium (10% activated carbon support) is added, and the mixture is hydrogenated at standard hydrogen pressure overnight. Turned into. The reaction mixture was then filtered through diatomaceous earth, the residue was washed with ethanol and the filtrate was concentrated. This gave 440 mg (purity 90%, 90% of theory) of the target compound.

LC-MS (Method 5): Rt = 0.19 min; MS (ESI cation): m / z = 191 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 4.02 (s, 3H), 4.88-4.96 (m, 2H), 6.73-6.77 (m, 1H ), 6.77-6.81 (m, 1H), 7.31 (d, 1H), 7.64 (br.s, 1H), 8.06 (br.s, 1H).

Example 81A
1- (2-carbamoyl-1-methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  In the same manner as in Example 31A, the target compound was produced and purified. 440 mg (2.31 mmol) of 5-amino-1-methyl-1H-benzimidazole-2-carboxamide from Example 80A and 600 mg (2.31 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate Starting from 158 mg (purity 87%, 17% of theory) of the title compound were obtained. The crude product was converted without further purification.

LC-MS (Method 1): Rt = 0.55 min; MS (ESI cation): m / z = 358 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 4.13-4.21 (m, 5H), 7.46-7.53 (m, 1H ), 7.80 (d, 1H), 7.89-7.93 (m, 2H), 8.31-8.37 (m, 2H), 11.69 (s, 1H).

Example 82A
1- (1-Methyl-1H-benzimidazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  In the same manner as in Example 31A, the target compound was produced and purified. Starting from 1.00 g (6.79 mmol) of 1-methyl-1H-benzimidazol-6-amine and 1.76 g (6.79 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate, 1.03 g (48% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.36 min; MS (ESI cation): m / z = 315 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 4.01 (s, 3H), 4.19 (q, 2H), 7.61-7. 67 (m, 1H), 7.90-7.96 (m, 1H), 8.15 (s, 1H), 8.37 (s, 1H), 9.29-9.37 (m, 1H) 11.80 (s, 1H).

Example 83A
1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide

  First, 1.00 g (9.25 mmol) of 1,2-phenylenediamine and 2.67 g (27.74 mmol) of sulfamide were placed in 14 mL of pyridine and the mixture was stirred at 130 ° C. overnight. For workup, the reaction mixture was concentrated under reduced pressure and the residue was separated by flash silica gel chromatography (cyclohexane / ethyl acetate gradient 7: 1, 5: 1). This gave 659 mg (42% of theory) of the title compound.

LC-MS (Method 5): Rt = 0.51 min; MS (ESI cation): m / z = 171 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 6.76-6.83 (m, 2H), 6.85-6.91 (m, 2H), 10.95 (br.s) 2H).

Example 84A
1,3-dimethyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide

  First, 1.54 g (38.45 mmol) of sodium hydride (60% in mineral oil) in 41 mL of DMF was placed under argon, and then at 0 ° C., 1,3-dihydro-2 from Example 83A. , 1,3-benzothiadiazole 2,2-dioxide 2.62 g (15.38 mmol) in DMF (5 mL) was added dropwise and the reaction mixture was stirred at 0 ° C. for 30 min. Thereafter, 2.39 mL (38.45 mmol) of iodomethane was added dropwise to bring the reaction mixture to room temperature and stirred for 1 hour. For workup, water (200 mL) was added at 0 ° C. and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was extracted and stirred in MTBE, the solid was filtered, washed with MTBE and dried under high vacuum. This gave 1.89 g (62% of theory) of the title compound. The crude product was converted without further purification.

LC-MS (Method 1): Rt = 0.78 min; MS (ESI cation): m / z = 199 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.23 (s, 6H), 6.98-7.05 (m, 4H).

Example 85A
1,3-dimethyl-5-nitro-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide

  First, 1.88 g (9.52 mmol) of 1,3-dimethyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide from Example 84A was placed in 8 mL of acetic acid, then Concentrated nitric acid (0.60 mL, 9.52 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. For workup, the reaction mixture was added to ice water and the precipitated solid was filtered off with suction, washed with water and dried at 50 ° C. in vacuo. This gave 2.17 g (93% of theory) of the title compound.

LC-MS (method 1): Rt = 0.81 min; MS (ESI positive ion): m / z = 244 ( M + H) +.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.37-3.42 (m, 6H), 7.23 (d, 1H), 7.92 (d, 1H), 8. 03 (dd, 1H).

Example 86A
1,3-dimethyl-1,3-dihydro-2,1,3-benzothiadiazole-5-amine 2,2-dioxide

  The target compound was produced and purified in the same manner as Example 33A. The reaction time was 16 hours. Starting from 2.17 g (8.92 mmol) of 1,3-dimethyl-5-nitro-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide from Example 85A 851 mg (44% of theory) were obtained.

LC-MS (Method 1): Rt = 0.31 min; MS (ESI cation): m / z = 214 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.07 (s, 3H), 3.10 (s, 3H), 4.89-4.99 (m, 2H), 6. 18-6.24 (m, 2H), 6.70 (d, 1H).

Example 87A
1- (1,3-Dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydro Pyrimidine-5-carboxylate

  First, 1.03 g (3.99 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate and 1,3-dimethyl-1,3-dihydro-2,1,3 from Example 86A. -851 mg (3.99 mmol) of benzothiadiazole-5-amine 2,2-dioxide was placed in 30 mL of ethanol and heated to reflux for 2 hours. Next, at room temperature, 448 mg (3.99 mmol) of potassium tert-butoxide was added and the mixture was stirred at room temperature for 16 hours and at reflux for 5 hours. For workup, the reaction mixture was acidified with 1N hydrochloric acid and the solid formed was filtered, washed with water and ethyl acetate, and then dried in vacuo at 50 ° C. This gave 1.36 g (84% purity, 75% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.74 min; MS (ESI cation): m / z = 381 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.20-1.24 (m, 3H), 3.25 (s, 3H), 3.30 (s, 3H), 4. 17 (q, 2H), 7.12-7.19 (m, 2H), 7.24-7.28 (m, 1H), 8.29 (s, 1H), 11.71 (br.s, 1H).

Example 88A
1- (1,3-Benzothiazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  Analogously to Example 76A, 1.00 g (6.65 mmol) of 1,3-benzothiazol-6-amine and 1.72 g (6.65 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate. ) Was used to produce the target compound. For workup, the reaction mixture was mixed with water and 1N hydrochloric acid, the precipitated solid was filtered off with suction, washed with ethyl acetate and dried at 50 ° C. under reduced pressure. This gave 1.85 g (87% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.61 min; MS (ESI cation): m / z = 318 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 4.18 (q, 2H), 7.67 (dd, 1H), 8.20 (d, 1H), 8.36 (d, 1H), 8.42 (s, 1H), 9.53 (s, 1H), 11.76 (s, 1H).

Example 89A
1-methyl-6-nitro-3,4-dihydroquinolin-2 (1H) -one

  First, under argon, 1.00 g (5.20 mmol) of 6-nitro-3,4-dihydroquinolin-2 (1H) -one [see WO 2006/71940, 416 for preparation] is placed in 148 mL of THF. Then 229 mg (5.72 mmol) of sodium hydride (60% in mineral oil) was added at 0 ° C. and the mixture was stirred for 30 minutes. Thereafter, 0.36 mL (5.72 mmol) of iodomethane was added dropwise and the reaction mixture was stirred at room temperature overnight. For workup, the reaction mixture was diluted with ethyl acetate and the organic phase was washed twice with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was stirred with ethanol and the solid was filtered, washed with ethanol and dried under high vacuum overnight. This gave 535 mg (50% of theory) of the title compound. The crude product was converted without further purification.

LC-MS (Method 3): Rt = 0.88 min; MS (ESI cation): m / z = 207 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.60-2.66 (m, 2H), 3.02 (t, 2H), 3.31 (s, 3H), 7. 26-7.32 (m, 1H), 8.12-8.20 (m, 2H).

Example 90A
6-amino-1-methyl-3,4-dihydroquinolin-2 (1H) -one

  First, 1.10 g (5.33 mmol) of the nitro compound from Example 89A was placed in 36 mL of ethanol, then 170 mg (0.16 mmol) of palladium (10% activated carbon supported product) was added, and the mixture was heated at standard hydrogen pressure. Hydrogenated overnight. The reaction mixture was then filtered through diatomaceous earth, the residue was washed with ethanol and the filtrate was concentrated. This gave 936 mg (99% of theory) of the target compound. The crude product was converted without further purification.

LC-MS (Method 2): Rt = 0.73 min; MS (ESI cation): m / z = 177 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.43 (t, 2H), 2.69 (t, 2H), 3.16 (s, 3H), 4.79-4. 90 (m, 2H), 6.41-6.47 (m, 2H), 6.77 (d, 1H).

Example 91A
1- (1-Methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  In the same manner as in Example 31A, the target compound was produced and purified. 6-Amino-1-methyl-3,4-dihydroquinolin-2 (1H) -one from Example 90A [Synthesis described on WO2003 / 72553, pages 150-151] 935 mg (5.30 mmol) and 3-ethoxy Starting from 1.37 g (5.30 mmol) of ethyl 2-[(ethoxycarbonyl) carbamoyl] acrylate, 1.33 g (73% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.65 min; MS (ESI cation): m / z = 344 (M + H) ⁺ .

_{^{1 H NMR (400MHz, DMSO-}} d 6): δ [ppm] = 1.22 (t, 3H), 2.56-2.61 (m, are partly obscured by DMSO signal), 2. 87-2.94 (m, 2H), 3.28 (s, 3H), 4.17 (q, 2H), 7.20 (d, 1H), 7.35-7.41 (m, 2H) 8.25 (s, 1H), 11.68 (s, 1H).

Example 92A
1- (1-Methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5 Ethyl carboxylate

  First, 916 mg (3.53 mmol) ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate and 6-amino-1-methyl-1,4-dihydro-2H-3,1-benzoxazine-2 -On [for manufacturing, WO 2007/93904; p. 22, see step 3] 630 mg (3.53 mmol) was placed in 20 mL ethanol and heated to reflux for 1 hour. Thereafter, 397 mg (3.53 mmol) of potassium tert-butoxide were added at room temperature, and the reaction mixture was stirred at room temperature for 16 hours and under reflux for 3 hours. For workup, the mixture was acidified with 1N hydrochloric acid at room temperature and the solid formed was filtered, washed with MTBE and then dried in vacuo at 50 ° C. This gave 1.11 g (90% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.58 min; MS (ESI cation): m / z = 346 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 3.3 (s, partially hidden by water signal), 4.17 (q, 2H), 5.29 (s, 2H), 7.21 (d, 1H), 7.40-7.44 (m, 1H), 7.48-7.54 (m, 1H), 8.27. (S, 1H), 11.70 (s, 1H).

Example 93A
1- (4-Methylquinolin-7-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  In the same manner as in Example 31A, the target compound was produced and purified. 4-Methylquinoline-7-amine [for production, see Nasr, M .; et al. , J. et al. Med. Chem. 1988, vol. 31 (7), p. Starting from 987 mg (5.31 mmol) and ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate 1.37 g (5.31 mmol). %).

LC-MS (Method 1): Rt = 0.63 min; MS (ESI cation): m / z = 326 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (t, 3H), 2.88 (s, 3H), 4.19 (q, 2H), 7.79 (d, 1H), 7.93 (dd, 1H), 8.32 (d, 1H), 8.41 (d, 1H), 8.50 (s, 1H), 9.06 (d, 1H), 11. 82 (s, 1H).

Example 94A
1- (imidazo [1,2-a] pyridin-7-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  In the same manner as in Example 31A, the target compound was produced and purified. Imidazo [1,2-a] pyridin-7-amine [for preparation see Tetrahedron, 2002, vol. 58 (2), p. 295-308] starting from 500 mg (3.75 mmol) and 973 mg (3.75 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate, 1.11 g (94 of theory) %).

LC-MS (Method 1): Rt = 0.19 min; MS (ESI cation): m / z = 301 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (t, 3H), 4.21 (q, 2H), 7.60 (d, 1H), 8.21 (d, 2H), 8.39 (s, 1H), 8.48 (s, 1H), 8.96 (d, 1H), 11.91 (s, 1H).

Example 95A
1- (6-Fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 5-ethyl carboxylate

  660 mg (3.38 mmol) of 5-amino-6-fluoro-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one from Example 19A and 3-ethoxy-2-[(ethoxycarbonyl ) Carbamoyl] The target compound was prepared in the same manner as in Example 31A using 877 mg (3.38 mmol) of ethyl acrylate. The resulting crude product was purified by flash silica gel chromatography (dichloromethane / methanol gradient 54: 1-20: 1) to give 437 mg (36% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.62 min; MS (ESI cation): m / z = 363 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.32 (s, 3H), 3.36 (s, 3H), 4.18 (q, 2H), 7.40 (d, 1H), 7.48 (d, 1H), 8.40 (s, 1H), 11.85 (s, 1H).

Example 96A
(3-Chloro-4-methyl-2-thienyl) methanol

  To a solution of borane-tetrahydrofuran complex (1M solution in THF, 3.40 mL, 3.40 mmol), 200 mg (1.13 mmol) of 3-chloro-4-methylthiophene-2-carboxylic acid in small portions at room temperature under argon. In addition, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then carefully added to 1N hydrochloric acid until gas evolution ceased. The entire mixture was separated by preparative HPLC (Method 8). This gave 115 mg (62% of theory) of the title compound.

GC-MS (Method 6): Rt = 4.00 min; EI ⁺ : m / z = 162 (M) ^+
1 H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.12 (s, 3H), 4.58 (d, 2H), 5.57 (t, 1H), 7.25 (s, 1H).

Example 97A
4,6-difluoroindan-1-ol (racemic)

  146.3 mg (3.87 mmol) of sodium borohydride was added to a solution of 1.00 g (5.95 mmol) of 4,6-difluoro-2,3-dihydro-1H-inden-1-one in ethanol (15 mL) at room temperature. In addition, the reaction mixture was stirred at room temperature overnight. The mixture was mixed with ethyl acetate and water and shaken vigorously. The organic phase was removed, washed with saturated ammonium chloride solution and saturated sodium chloride solution, dried over magnesium sulfate, and the solvent was removed on a rotary evaporator. The residue was briefly dried under HV. This gave 950 mg (94% of theory) of the title compound.

GC-MS (Method 6): Rt = 3.35 min; MS (CI-cation): m / z = 170 (M) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.78-1.88 (m, 1H), 2.35-2.44 (m, 1H), 2.67 (dt, 1H ), 2.90 (ddd, 1H), 5.05 (q, 1H), 5.49 (d, 1H), 6.99 (dd, 1H), 7.04 (td, 1H).

Example 98A
6-Fluoro-4- (trifluoromethyl) indan-1-ol (racemic)

  Sodium borohydride (23.3 mg, 0.62 mmol) was treated with 6-fluoro-4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-one (Production: US2011 / 53974, page 77, Examples) 61C) To a solution of 207 mg (0.95 mmol) in ethanol (6 mL) at room temperature was added and the reaction mixture was stirred at room temperature overnight. The mixture was mixed with ethyl acetate and 1N hydrochloric acid and shaken vigorously. The organic phase was removed and washed with 1N hydrochloric acid, then with saturated sodium chloride solution, dried over sodium sulfate, and the solvent was completely removed on a rotary evaporator. This gave 203 mg (97% of theory) of the title compound.

GC-MS (Method 6): Rt = 3.19 min; MS (CI-cation): m / z = 220 (M) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ )): δ [ppm] = 1.84-1.96 (m, 1H), 2.43-2.54 (m, 1H), 2.82 (dt, 1H), 3.02-3.14 (m, 1H), 5.14 (t, 1H), 7.17 (d, 1H), 7.21 (d, 1H).

Example 99A
7- (Trifluoromethyl) -2,3-dihydro-1-benzofuran-3-ol (racemic)

  In the same manner as in Example 98A, 7- (trifluoromethyl) -2,3-dihydro-1-benzofuran-3-one (Production: US2011 / 53974, page 56, see Example 47E) 388 mg (1.92 mmol) Was reduced with sodium borohydride. This gave 210 mg (51% of theory) of the title compound.

GC-MS (Method 6): Rt = 3.80 min; MS (CI-cation): m / z = 204 (M) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 4.38 (dd, 1H), 4.66 (dd, 1H), 5.33 (dd, 1H), 5.72-5. 91 (br.m, 1H), 7.07 (t, 1H), 7.52 (d, 1H), 7.66 (d, 1H).

Example 100A
6-Methylindan-1-ol (racemic)

  In the same manner as in Example 97A, 1.00 g (6.84 mmol) of 6-methyl-2,3-dihydro-1H-inden-1-one was reduced with sodium borohydride. This gave 950 mg (94% of theory) of the title compound.

GC-MS (Method 6): Rt = 3.89 min; MS (CI-cation): m / z = 148 (M) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.74 (dddd, 1H), 2.25 to 2.35 (m, 1H), 2.64 (dt, 1H), 2. 84 (ddd, 1H), 4.99 (q, 1H), 5.14 (d, 1H), 6.99 (br.d, 1H), 7.08 (d, 1H), 7.12 (s 1H).

Example 101A
6- [5- (Ethoxycarbonyl) -2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl] -3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole 1-carboxylate tert-butyl

  A suspension of 8.00 g (24.2 mmol) of the compound from Example 36A and 30 mg (0.24 mmol) of DMAP in DMF (500 mL) and dichloromethane (100 mL) at room temperature with 6.12 mL of di-tert-butyl dicarbonate (100 mL). 26.6 mmol) and stirred at room temperature overnight. For workup, 1.6 liters of water was added and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were washed twice with water, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was stirred with diethyl ether and the precipitated product was isolated by filtration and dried under HV. This gave 6.00 g (58% of theory) of the title compound.

LC-MS (Method 4): Rt = 1.80 min; m / z = 431 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 1.58 (s, 9H), 4.17 (q, 2H), 7.28-7. 40 (m, 2H), 7.84 (d, 1H), 8.25 (s, 1H), 11.65 (s, 1H) (probably the methyl group under the DMSO signal).

Example 102A
5-Methoxyindan-1-ol (racemic)

  In the same manner as in Example 97A, 1.00 g (6.17 mmol) of 5-methoxy-2,3-dihydro-1H-inden-1-one was reduced with sodium borohydride. This gave 930 mg (purity 80%, 73% of theory) of the title compound.

GC-MS (Method 6): Rt = 4.70 min; MS (CI-cation): m / z = 164 (M) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.7-1.82 (m, 1H), 2.25-2.34 (m, 1H), 2.61-2.72 (M, 1H), 2.83-2.93 (m, 1H), 3.72 (s, 3H), 4.97 (q, 1H), 5.05 (d, 1H), 6.71- 6.76 (m, 1H), 6.77 (br.s, 1H), 7.21 (d, 1H).

Example 103A
4-Methoxyindan-1-ol (racemic)

  In the same manner as in Example 97A, 1.00 g (6.17 mmol) of 4-methoxy-2,3-dihydro-1H-inden-1-one was reduced with sodium borohydride. This gave 910 mg (90% of theory) of the title compound.

GC-MS (Method 6): Rt = 4.65 min; MS (CI-cation): m / z = 164 (M) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.68-1.80 (m, 1H), 2.25-2.35 (m, 1H), 2.54-2.62 (M, 1H), 2.83 (ddd, 1H), 3.76 (s, 3H), 5.02 (q, 1H), 5.18 (d, 1H), 6.80 (d, 1H) 6.93 (d, 1H), 7.17 (t, 1H).

Example 104A
(2E) -3- [4-Chloro-2- (trifluoromethyl) phenyl] methyl acrylate

  4-chloro-1-iodo-2- (trifluoromethyl) benzene 8.00 g (26.1 mmol), methyl acrylate 3.76 mL (41.8 mmol), tetra-n-butylammonium chloride 7.47 g (26. 9 mmol), 117 mg (0.52 mmol) of palladium (II) acetate and 7.22 g (52.2 mmol) of potassium carbonate in (80 mL) DMF were stirred at room temperature for 3 days. The mixture was diluted with 1 liter of diethyl ether and washed 3 times with 200 mL each time with water. The organic phase was dehydrated with sodium sulfate and concentrated on a rotary evaporator. The residue solidified after a while. This gave 6.65 g (92% of theory) of the title compound.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.76 (s, 3H), 6.81 (d, 1H), 7.79 (dq, 1H), 7.84 (dd, 1H), 7.91 (d, 1H), 8.12 (d, 1H).

Example 105A
3- [4-Chloro-2- (trifluoromethyl) phenyl] propanoic acid methyl ester

  6.65 g (25.1 mmol) of the compound from Example 104A was hydrogenated in 250 mL of ethyl acetate in the presence of 2 g of palladium (10% carbon supported product) under atmospheric pressure hydrogen for 2 days. The catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated on a rotary evaporator. This gave 5.26 g (59% of theory) of the title compound with a purity of about 75%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.6-2.68 (m, 2H), 3.01 (t, 2H), 3.61 (s, 3H), 7. 56 (d, 1H), 7.69-7.76 (m, 2H).

Example 106A
3- [4-Chloro-2- (trifluoromethyl) phenyl] propanoic acid

  A solution of 5.26 g (19.7 mmol) of the compound from Example 105A in methanol (150 mL) was mixed with 59.2 mL (59.2 mmol) of 1M sodium hydroxide solution and stirred at room temperature for 2 hours. Methanol was removed on a rotary evaporator. The remaining aqueous residue was diluted with 600 mL of water and filtered. The filtrate was acidified with 1M hydrochloric acid. The precipitated solid was filtered off with suction, washed with water and dried under HV. This gave 4.45 g (80% of theory) of the title compound with a purity of about 90%.

LC-MS (Method 5): Rt = 1.02 min; MS (ESI-anion): m / z = 251 (M−H) ⁻ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.5-22.58 (m, 2H, partly hidden under DMSO signal), 2.97 (t, 2H), 7.56 (d, 1H), 7.68-7.76 (m, 2H), 12.32 (br.s, 1H).

Example 107A
6-Chloro-4- (trifluoromethyl) indan-1-one

  4.08 g (purity 92%, 14.8 mmol) of the compound from Example 106A was mixed with 44 mL of chlorosulfonic acid with ice cooling and then stirred at room temperature for 5 hours. The reaction mixture was then added dropwise to 600 g of carefully crushed ice (very exothermic). The mixture was extracted 3 times with dichloromethane. The combined organic phases were washed twice with 1M sodium carbonate solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried very briefly under HV. This gave 2.38 g (63% of theory) of the title compound with a purity of about 92%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.73-2.82 (m, 2H), 3.19-3.28 (m, 2H), 7.96 (s, 1H ), 8.13 (s, 1H).

Example 108A
6-chloro-4- (trifluoromethyl) indan-1-ol (racemic)

  In the same manner as Example 98A, 2.38 g (10.1 mmol) of 6-chloro-4- (trifluoromethyl) indan-1-one from Example 107A was reduced with sodium borohydride. This gave 1.97 g (82% of theory) of the title compound.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.79-1.92 (m, 1H), 2.35-2.47 (m, 1H), 2.84 (dt, 1H ), 2.98-3.10 (m, 1H), 5.09 (q, 1H), 5.58 (d, 1H), 7.64 (br.d, 2H).

Example 109A
(2E) -3- [4-Bromo-2- (trifluoromethyl) phenyl] methyl acrylate

  Analogously to Example 104A, 8.00 g (22.8 mmol) of 4-bromo-1-iodo-2- (trifluoromethyl) benzene was reacted with 3.29 mL (36.5 mmol) of methyl acrylate to give the product Was isolated. The crude product was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 10: 1). This gave 5.70 g (81% of theory) of the title compound.

GC-MS (Method 6): Rt = 4.75 min; MS (CI-cation): m / z = 308/310 (M) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.76 (s, 3H), 6.82 (d, 1H), 7.77 (dq, 1H), 7.94-8. 07 (m, 3H).

Example 110A
3- [4-Bromo-2- (trifluoromethyl) phenyl] propanoic acid methyl ester

First, 5.70 g (18.4 mmol) of the compound from Example 109A was hydrogenated in the same manner as Example 105A using palladium (10% carbon supported product) under atmospheric pressure hydrogen. Monitoring the reaction by LC-MS revealed that there was no reduction of the double bond and about 25% debromination occurred. Hydrogenation was stopped, the catalyst was filtered and the solvent was removed on a rotary evaporator. The reaction product (5.0 g) recovered in this manner was added to [Rh {(S, S) -Phebox-iPr} (OAc) ₂ ] .H ₂ O (manufactured by H. Nishiyama et al, Chem. Eur. J. 2006, 12 (1), 63-71, see Example 3a) with 87 mg (0.16 mmol) in 30 mL toluene to 60 ° C., at this temperature 3.89 mL (24.26 mmol) methyldiethoxysilane ). The mixture was further stirred at 60 ° C. for 4 hours and then stirred at reflux temperature overnight. After cooling to room temperature, the mixture was mixed with 50 mL of 1N hydrochloric acid and extracted with 150 mL of ethyl acetate. The organic phase was washed twice with water, twice with saturated sodium hydrogen carbonate solution and once with saturated sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue corresponded to the title compound (5.84 g, 93% of theory) with a purity of about 80% and was further transformed without purification.

GC-MS (method 6): Rt = 4.42 min; MS (CI-cation): m / z = 310/312 (M) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 2.5-2.64 (m, 2H), 3.07 (t, 2H), 3.66 (s, 3H), 7. 27 (d, 1H), 7.63 (d, 1H), 7.78 (d, 1H).

Example 111A
3- [4-Bromo-2- (trifluoromethyl) phenyl] propanoic acid

  Analogously to Example 106A, 5.60 g (18 mmol) of the compound from Example 110A was converted and isolated. This gave 3.42 g (54% of theory) of the title compound with a purity of about 85%.

LC-MS (Method 4): Rt = 2.25 min; MS (ESI cation): m / z = 295/297 (M−H) ⁻ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.5-22.58 (m, 2H, partly hidden under DMSO signal), 2.95 (t, 2H), 7.49 (d, 1H), 7.81-7.88 (m, 2H), 12.37 (br.s, 1H).

Example 112A
6-Bromo-4- (trifluoromethyl) indan-1-one

  Analogously to Example 107A, 3.42 g (purity 85%, 9.8 mmol) of the compound from Example 111A was converted and isolated. This gave 2.10 g (69% of theory) of the title compound with a purity of about 90%.

GC-MS (Method 6): Rt = 4.34 min; MS (CI-cation): m / z = 278/280 (M) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 2.75-2.82 (m, 2H), 3.23-31 (m, 2H), 7.96 (s, 1H), 8.05 (s, 1H).

Example 113A
6-Bromo-4- (trifluoromethyl) indan-1-ol (racemic)

  A solution of 500 mg (1.79 mmol) of the compound from Example 112A in ethanol (3.9 mL) was mixed with 44.0 mg (1.16 mmol) of sodium borohydride and stirred at room temperature overnight. 3 mL of 1N hydrochloric acid was added and the mixture was stirred for several minutes and then completely separated by HPLC (Method 7). Fractions containing product were concentrated completely under reduced pressure and the residue was dried under HV. This gave 352 mg (92% of theory) of the title compound.

GC-MS (Method 6): Rt = 4.58 min; MS (CI-cation): m / z = 280/282 (M) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.79-1.90 (m, 1H), 2.35-2.46 (m, 1H), 2.82 (dt, 1H ), 2.97-3.07 (m, 1H), 5.09 (q, 1H), 5.57 (dd, 1H), 7.74 (br.s, 1H), 7.77 (br. s, 1H).

Example 114A
4,6-dichloroindan-1-ol (racemic)

  In the same manner as in Example 98A, 1.25 g (6.22 mmol) of 4,6-dichloroindan-1-one was reduced with sodium borohydride, and the product was isolated. This gave 1.20 g (95% of theory) of the title compound.

MS (Method _{26DCI / NH 3): m /} z = 202 (M +).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.75-1.90 (m, 1H), 2.30-2.44 (m, 1H), 2.64-2.78 (M, 1H), 2.85-2.98 (m, 1H), 5.09 (q, 1H), 5.53 (d, 1H), 7.32 (s, 1H), 7.44 ( d, 1H).

Example 115A
1- [2-Methyl-3- (trifluoromethyl) phenyl] ethanol

  4.25 mL of methylmagnesium bromide solution (3M solution in diethyl ether, 12.75 mmol) was added dropwise to a solution of 2.00 g (10.6 mmol) of 2-methyl-3- (trifluoromethyl) benzaldehyde in diethyl ether (50 mL). In the middle of the reaction, the reaction mixture was heated to the reflux temperature. After the addition was complete, the reaction mixture was heated to reflux for an additional hour. After cooling to room temperature, a small piece of ice was added and 6N hydrochloric acid was then added dropwise until the precipitate that formed was dissolved again. The phases were separated. The aqueous phase was extracted once more with diethyl ether. The combined organic phases were dehydrated with magnesium sulfate and concentrated on a rotary evaporator. This gave 2.40 g (100% of theory, still containing about 10% diethyl ether according to NMR) of the title compound.

¹ H NMR (500 MHz, CDCl ₃ ): δ [ppm] = 1.48 (d, 3H), 5.25 (q, 1H), 7.32 (t, 1H), 7.56 (d, 1H) 7.76 (d, 1H).

Example 116A
1- [2-Chloro-3- (trifluoromethyl) phenyl] ethanol

  In the same manner as in Example 115A, 2.00 g (9.59 mmol) of 2-methyl-3- (trifluoromethyl) benzaldehyde was reacted with methylmagnesium bromide. This gave 2.40 g of the title compound (89% of theory, still containing about 20% diethyl ether according to NMR).

¹ H NMR (500 MHz, CDCl ₃ ): δ [ppm] = 1.51 (d, 3H), 5.41 (q, 1H), 7.41 (t, 1H), 7.62 (d, 1H) 7.85 (d, 1H).

Example 117A
1- (1-ethyl-2-methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  First, 1.04 g (4.03 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate and 1.00 g of 1-ethyl-2-methyl-1H-benzimidazol-5-amine dihydrochloride (4.03 mmol) was placed in 30 mL of ethanol, then 1.24 mL (8.87 mmol) of triethylamine was added and the mixture was heated to reflux for 2 hours. Then, at room temperature, 452 mg (4.03 mmol) of potassium tert-butoxide was added and the reaction mixture was first stirred at room temperature overnight and then heated to reflux and stirred at this temperature overnight. For workup, the reaction mixture was mixed with water and acidified with 1N hydrochloric acid. The mixture was concentrated to dryness and the residue was stirred with dichloromethane / methanol (1: 1) and filtered. The filtrate was concentrated again, the residue was stirred with MTBE / ethyl acetate and the solid formed was filtered. After drying under HV, 1.07 g (purity 87%, 68% of theory) of the target compound was obtained.

LC-MS (Method 2): Rt = 1.06 min; MS (ESI cation): m / z = 343 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.41 (t, 3H), 2.84 (s, 3H), 4.18 (q, 2H), 4.47 (q, 2H), 7.64-7.70 (m, 1H), 7.99-8.02 (m, 1H), 8.06 (d, 1H), 8.35. (S, 1H), 11.75 (s, 1H).

Example 118A
1- (1-cyclohexyl-2-methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  First, 0.86 g (3.31 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylate and 1.00 g of 1-cyclohexyl-2-methyl-1H-benzimidazol-5-amine dihydrochloride (3.31 mmol) was placed in 25 mL of ethanol and the mixture was heated to reflux for 2 hours. Next, at room temperature, 371 mg (3.31 mmol) of potassium tert-butoxide was added and the reaction mixture was stirred at room temperature overnight and under reflux for 5 days. For workup, the reaction mixture was mixed with water, acidified with 1N hydrochloric acid and then concentrated on a rotary evaporator. The residue was stirred in dichloromethane / methanol (1: 1) and the insoluble residue was filtered. The filtrate was concentrated and mixed with ethanol and the solid formed was filtered and dried. This gave 1.85 g of the title compound as a crude product that was converted without further purification.

LC-MS (Method 1): Rt = 0.72 min; MS (ESI cation): m / z = 397 (M + H) ⁺ .

Example 119A
1- (4-Methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5 Ethyl carboxylate

  First, 7-amino-4-methyl-2H-1,4-benzoxazin-3 (4H) -one 2.00 g (11.2 mmol) and 3-ethoxy-2-[(ethoxycarbonyl) carbamoyl] acrylic acid 2.65 g (10.2 mmol) of ethyl was placed in 100 mL of ethanol and the mixture was heated to reflux for 2 hours. After cooling to room temperature, 1.15 g (10.2 mmol) of potassium tert-butoxide was added and the reaction mixture was further stirred at room temperature for 2 days and then at reflux temperature for 1 hour. For workup, the reaction mixture was diluted with water and acidified with 1M hydrochloric acid. The formed solid was filtered, washed with water and dried under HV. This gave 2.79 mg (70% of theory) of the title compound.

LC-MS (Method 3): Rt = 0.76 min; MS (ESI cation): m / z = 346 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 4.17 (q, 2H), 4.71 (s, 2H), 7.18-7. 23 (m, 2H), 7.28 (d, 1H), 8.22 (s, 1H), 11.68 (s, 1H).

Example 120A
8-Chloro-3,4-dihydro-1H-isochromen-4-ol

  270 mg (1.48 mmol) of 8-chloro-1H-isochromen-4 (3H) -one (reactant produced in-house, not described in literature but available from ACD supplier with catalog number and CAS number) To a solution in methanol (5 mL), 224 mg (5.91 mmol) of sodium borohydride was added at room temperature and the mixture was stirred at room temperature for 1 hour. Next, 5 mL of 1N aqueous hydrochloric acid was added and the mixture was stirred for an additional 10 minutes, then separated by preparative HPLC (Method 15). Acetonitrile was removed from the suitable fractions at 130 mbar on a rotary evaporator and the remaining aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate and concentrated on a rotary evaporator at 130 mbar. This gave 400 mg of the title compound, which still contains acetonitrile and dichloromethane according to NMR. It was used as such for the preparation of Example 302.

LC / MS (Method 4): Rt = 1.69 min; m / z = 167 (M-OH) ^<+> .

¹ H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 2.57 (br.s, 1H), 3.85 (dd, 1H), 4.09 (dd, 1H), 4.56 (br. s., 1H), 4.62 (d, 1H), 4.89 (d, 1H), 7.22-7.35 (m, 2H), 7.39 (d, 1H).

Working example:
Example 1
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) -benzyl] -2,4 -Ethyl dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 2A To a solution of 14.95 g (43.42 mmol) of ethyl-5-carboxylate in DMF (200 mL), 12.00 g (86.84 mmol) of potassium carbonate, 12.09 g of 2-methyl-3- (trifluoromethyl) benzyl bromide (47.76 mmol) and 0.721 g (4.34 mmol) of potassium iodide were added and the reaction mixture was stirred at 80 ° C. for 3 hours. The mixture was then cooled to room temperature, water was added and the resulting precipitate was filtered. The solid was washed sequentially with water and MTBE and vacuum dried at 50 ° C. This gave 21.04 g (94% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.07 min; m / z = 517 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 2.46 (s, 3H), 3.34 (s, 3H), 3.37 (s, 3H), 4.20 (q, 2H), 5.09 (s, 2H), 7.23-7.30 (m, 2H), 7.32-7.43 (m, 3H), 7.58 -7.62 (m, 1H), 8.42 (s, 1H).

  In the same manner as in Example 1, using the above 1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxylic acid ester (uracil-5-carboxylic acid ester), potassium carbonate and iodide The following benzyl-substituted uracil compounds were obtained by reaction with individual benzyl chlorides or benzyl bromides in the presence of potassium. The difference is that 1 to 3 equivalents of potassium carbonate and 0.1 to 2 equivalents of potassium iodide can also be used. In view of sufficiently soluble compounds, acetonitrile was used as the solvent in some cases.

Example 2
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 1. 1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 2A Starting from 200 mg (0.58 mmol) ethyl-5-carboxylate and 175 mg (0.64 mmol) 2-chloro-3- (trifluoromethyl) benzyl bromide, 234 mg (73% of theory) of the title compound were obtained. .

LC-MS (Method 1): Rt = 1.08 min; m / z = 537 (M + H) ^<+> .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.34 (s, 3H), 3.37 (s, 3H), 4.20 (d, 2H), 5.16 (s, 2H), 7.27 (s, 2H), 7.39-7.42 (m, 1H), 7.50-7.60 (m, 2H), 7.78. -7.83 (m, 1H), 8.44 (s, 1H).

Example 3
3- (2,3-Dichlorobenzyl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2, 3,4-Tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was produced and purified in the same manner as Example 1 using acetonitrile as a solvent. 1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 2A Starting from 200 mg (0.58 mmol) of ethyl 5-carboxylate and 125 mg (0.64 mmol) of 2,3-dichlorobenzyl chloride, 241 mg (79% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.05 min; m / z = 503 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.34 (s, 3H), 3.37 (s, 3H), 4.20 (q, 2H), 5.11 (s, 2H), 7.20-7.29 (m, 3H), 7.31-7.36 (m, 1H), 7.39-7.41 (m, 1H) 7.56-7.60 (m, 1H), 8.43 (s, 1H).

Example 4
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-fluoro-3- (trifluoromethyl) benzyl] -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 1. 1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 2A Starting from 200 mg (0.58 mmol) of ethyl-5-carboxylate and 164 mg (0.64 mmol) of 2-fluoro-3- (trifluoromethyl) benzyl bromide, 162 mg (53% of theory) of the title compound were obtained. .

LC-MS (Method 1): Rt = 1.13 min; m / z = 521 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 1.23 (t, 3H), 3.33 (s, 3H), 3.34 (s, 3H), 4.20 (d, 2H), 5.15 (s, 2H), 7.19-7.31 (m, 2H), 7.31-7.44 (m, 2H), 7.68 (d, 2H), 8.40 (s, 1H).

Example 5
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [3-fluoro-2- (trifluoromethyl) -benzyl] -2,4 -Ethyl dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 1. 179 mg (0.52 mmol) of ethyl 1- (4-methoxyphenyl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 2A and 3-fluoro-2-tri Starting from 147 mg (0.57 mmol) of fluorobenzyl bromide, 207 mg (74% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.12 min; m / z = 521 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.34 (s, 3H), 3.37 (s, 3H), 4.20 (q, 2H), 5.21 (s, 2H), 7.17-7.22 (m, 1H), 7.22-7.30 (m, 2H), 7.37-7.44 (m, 2H) , 7.63-7.71 (m, 1H), 8.45 (s, 1H).

Example 6
3- (2-Chloro-3,6-difluorobenzyl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  Initially, 150 mg (0.43 mmol) of the compound from Example 5A was mixed with acetonitrile (2. 06 mL). Next, molecular sieves (3Å), copper (II) acetate 118 mg (0.65 mmol) and DMSO 0.13 mL (1.83 mmol) were added and the reaction mixture was stirred in a sealed vessel at 80 ° C. for 3 days. For workup, the reaction mixture was mixed with ethyl acetate, then washed twice with hydrochloric acid (1M), once with saturated sodium bicarbonate solution, and once with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was stirred with methanol and the solid was filtered off with suction, washed with methanol and dried at 50 ° C. under reduced pressure. This gave 114 mg (purity 84%, 44% of theory) of the title compound.

LC-MS (Method 2): Rt = 2.06 min; m / z = 505 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 4.16 (q, 2H), 5.21 (s, 2H), 7.16 (d, 1H), 7.22-7.31 (m, 2H), 7.34 (s, 1H), 7.38-7.48 (m, 1H), 8.36 (s, 1H).

Example 7
3- (3-Chloro-2-methylbenzyl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1, 2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  First, the compound from 150 mg (0.46 mmol) of Example 7A was placed in acetonitrile (4.00 mL) along with 267 mg (0.93 mmol) of the boronate ester from Example 3A and 0.19 mL (1.39 mmol) of triethylamine. It was. Next, molecular sieves (3Å), 126 mg (0.69 mmol) of copper (II) acetate and 0.13 mL (1.83 mmol) of DMSO were added, and the reaction mixture was stirred at 80 ° C. in a sealed container for 1 day. For workup, the mixture was mixed with ethyl acetate and then washed twice with 1M hydrochloric acid, once with saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was stirred with MTBE, the solid was filtered off with suction and dried at 50 ° C. under reduced pressure. This solid was purified by preparative HPLC (Method 8). This gave 78 mg (35% of theory) of the title compound.

LC-MS (Method 3): Rt = 1.34 min; m / z = 483 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 2.41 (s, 3H), 3.34 (s, 3H), 3.37 (s, 3H), 4.19 (q, 2H), 5.05 (s, 2H), 7.05 (d, 1H), 7.17 (t, 1H), 7.22-7.30 (m, 2H) ), 7.35 (d, 1H), 7.41 (d, 1H), 8.40 (s, 1H).

Example 8
3- [2,3-Bis (trifluoromethyl) benzyl] -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo -1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  First, 150 mg (0.37 mmol) of the compound from Example 10A was mixed with acetonitrile (4. 4) with 248 mg (purity 85%, 0.73 mmol) of the boronate ester from Example 3A and 0.15 mL (1.10 mmol) of triethylamine. 00 mL). Next, molecular sieves (3Å), 100 mg (0.54 mmol) of copper (II) acetate and 0.13 mL (1.83 mmol) of DMSO were added, and the reaction mixture was stirred at 80 ° C. in a sealed container for 3 days. For workup, the reaction mixture was diluted with ethyl acetate and then washed twice with 1M hydrochloric acid and once with saturated sodium bicarbonate solution and saturated sodium chloride solution, respectively. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was separated by preparative HPLC (Method 8). Fractions containing product were partially concentrated on a rotary evaporator. The precipitated solid was filtered, washed with water and dried under high vacuum. This gave 127 mg (61% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.05 min; m / z = 571 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.2-3.4 (2 s, partially hidden by water signal); 20 (q, 2H), 5.25 (br.s, 2H), 7.26 (q, 2H), 7.39 (s, 1H), 7.73 (d, 1H), 7.85 (t 1H), 7.98 (d, 1H), 8.46 (s, 1H).

Example 9
3- (3-Chloro-5-fluorobenzyl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1, 2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 1. The reaction time was 1 hour. 1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 2A Starting from 200 mg (0.58 mmol) of ethyl-5-carboxylate and 142 mg (0.63 mmol) of 1- (bromomethyl) -3-chloro-5-fluorobenzene, 255 mg (90% of theory) of the title compound are obtained. It was.

LC-MS (Method 1): Rt = 0.97 min; m / z = 487 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 1.23 (t, 3H), 3.34 (s, 3H), 3.37 (s, 3H), 4.19 (q, 2H), 5.03 (s, 2H), 7.19 (d, 1H), 7.22-7.25 (m, 1H), 7.27 (s, 1H), 7.28-7.31 (m, 1H), 7.32-7.37 (m, 1H), 7.40 (d, 1H), 8.36 (s, 1H).

Example 10
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [3-fluoro-5- (trifluoromethyl) benzyl] -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 1. The reaction time was 1 hour. 1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 2A Starting from 200 mg (0.58 mmol) of ethyl-5-carboxylate and 164 mg (0.63 mmol) of 1- (bromomethyl) -3-fluoro-5- (trifluoromethyl) benzene, 278 mg (91 of theory) %).

LC-MS (Method 1): Rt = 1.01 min; m / z = 521 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 1.23 (s, 3H), 3.31 (s, 3H), 3.37 (s, 3H), 4.20 (q, 2H), 5.12 (s, 2H), 7.23 (dd, 1H), 7.28 (d, 1H), 7.39 (d, 1H), 7.52 (d, 1H), 7.58-7 .63 (m, 2H), 8.37 (s, 1H).

Example 11
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [4- (trifluoromethyl) -2,3- Dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

  Method A: The title compound was prepared and purified as in Example 8. The reaction time was 4 days. 2,4-Dioxo-3- [4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5 from Example 21A 300 mg of ethyl carboxylate (purity 80%, 0.65 mmol) and 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl from Example 3A ) -1,3-dihydro-2H-benzimidazol-2-one starting from 375 mg (1.30 mmol) and after further purification by flash chromatography (dichloromethane / methanol 98: 2), the title compound 190 mg (theoretical) Of 52%).

LC-MS (Method 5): Rt = 1.08 min; m / z = 529 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 2.35-2.43 (m, 1H), 2.44-2.48 (m, 1H) ), 3.03-3.15 (m, 1H), 3.21-3.29 (m, 1H), 3.31 (s, 3H), 3.36 (s, 3H), 4.18 ( q, 2H), 6.35-6.58 (m, 1H), 7.13-7.28 (m, 2H), 7.37 (t, 2H), 7.45-7.55 (m, 2H), 8.33 (s, 1H).

  Method B: In another experiment, 1.00 g of the compound from Example 21A was used in the same manner. However, after purification by flash chromatography, the product (1.20 g) was only 63% pure (corresponding to about 50% of theory). This is separated directly into the enantiomers by preparative chiral HPLC (Method 12), the first eluting enantiomer 377 mg (24% of theory) (see Example 12) and the later eluting enantiomer 31 mg (21% of theory) ) (See Example 13).

Example 12
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3-[(1S) -4- (trifluoromethyl)- 2,3-Dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (S enantiomer)

  Method A: First eluting enantiomer (377 mg) from separation of compound from Example 11 (Method B) by preparative HPLC in chiral phase (Method 12).

  Chiral HPLC (Method 13): Rt = 9.39 min, 100% ee.

Specific rotation: α _D ²⁰ = −117.1 ° (acetonitrile, c = 0.05 g / 100 mL).

  Method B: First, 5.68 g (16.49 mmol) of the compound from Example 2A and 4.00 g of (1R) -4- (trifluoromethyl) indan-1-ol from Example 15A under an argon atmosphere. 19.79 mmol) and 7.78 g (29.68 mmol) of triphenylphosphine were placed in 200 mL of DMF and 100 mL of THF and cooled to 0 ° C. 5.19 mL (5.33 g, 26.4 mmol) of diisopropyl azodicarboxylate was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 2 hours. Then 25 mL of 1N hydrochloric acid was added and the mixture was stirred for 15 minutes. For workup, about 2 liters of ethyl acetate and 1.33 liters of dilute hydrochloric acid (about 2.5N) were added. After stirring, the organic phase was separated, washed twice with dilute hydrochloric acid, once with 1N sodium carbonate solution and once with saturated sodium chloride solution and dried over sodium sulfate. The solvent was removed on a rotary evaporator. The residue was purified by preparative HPLC (Method 11). This gave 5.15 g (59% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.04 min; m / z = 529 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.31 (t, 3H), 2.36-2.51 (m, 1H), 2.59 (ddt, 1H), 3. 07-3.20 (m, 1H), 3.39 (s, 3H), 3.40 (s, 3H), 3.42-3.54 (m, 1H), 4.29 (q, 2H) 6.57-6.68 (br.m, 1H), 6.94 (br.s, 1H), 7.02 (s, 2H), 7.25-7.38 (m, 2H), 7 .49 (d, 1H), 8.31 (s, 1H).

  Chiral HPLC (Method 13): Rt = 9.39 min, 92% ee.

Example 13
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3-[(1R) -4- (trifluoromethyl)- 2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer)

  Method A: Enantiomer (331 mg) eluting last from separation of the compound from Example 11 (Method B) by preparative HPLC in chiral phase (Method 12).

  Chiral HPLC (Method 13): Rt = 11.12 min, 92% ee.

  Method B: First, 1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2, from Example 2A 3.05 g (8.86 mmol) of ethyl 3,4-tetrahydropyrimidine-5-carboxylate, 2.15 g (10.63 mmol) of (1S) -4- (trifluoromethyl) indan-1-ol from Example 14A And 6.97 g (26.6 mmol) of triphenylphosphine were placed in THF / DMF 1: 1 (1.7 liters) under argon and cooled to −15 ° C. 3.48 mL (17.71 mmol) of diisopropyl azodicarboxylate was gradually added. The reaction mixture was then stirred for an additional 30 minutes at room temperature. While cooling with ice, an additional 0.8 equivalents (1.39 mL, 6.86 mmol) of diisopropyl azodicarboxylate was added dropwise and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to −40 ° C., mixed with 1M hydrochloric acid, diluted with ethyl acetate and stirred vigorously for several minutes. The organic phase was separated, washed twice with 1M sodium carbonate solution and once with saturated sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was mixed with MTBE and stirred overnight at room temperature, then stirred for 20 minutes with ice bath cooling. The precipitated solid was filtered off with suction and washed with cold MTBE. The entire filtrate was concentrated and purified by preparative HPLC (Method 7). This gave 2.90 g (62% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.05 min; m / z = 529 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ = 1.36 (t, 3H), 2.42-2.55 (m, 1H), 2.57-2.71 (m, 1H), 3 .12-3.24 (m, 1H), 3.43 (s, 3H), 3.43-3.58 (m, 1H), 3.45 (s, 3H), 4.33 (q, 2H) ), 6.60-6.73 (m, 1H), 6.99 (s, 1H), 7.07 (s, 2H), 7.30-7.42 (m, 2H), 7.54 ( d, 2H), 8.36 (s, 1H).

Example 14
1- (1-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) -benzyl] -2,4-dioxo -1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 1. The reaction time was 1 hour. 1- (1-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5 from Example 36A Starting from 500 mg (1.51 mmol) of ethyl carboxylate and 421 mg (1.67 mmol) of 2-methyl-3- (trifluoromethyl) benzyl bromide, 606 mg (purity approx. 83%, 66% of theory) of the title compound Got.

LC-MS (Method 1): Rt = 0.96 min; m / z = 503 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 2.46 (s, 3H), 3.30 (s, partly hidden by water signal 4.19 (q, 2H), 5.07 (s, 2H), 7.18-7.23 (m, 3H), 7.31-7.42 (m, 2H), 7.57 -7.62 (m, 1H), 8.39 (s, 1H), 11.13 (s, 1H).

Example 15
3- (2,3-Dichlorobenzyl) -1- (1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3 4-tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 1. The reaction time was 5 hours. 1- (1-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5 from Example 36A -After further purification by preparative HPLC (Method 8) starting from 200 mg (0.61 mmol) of ethyl carboxylate and 130 mg (0.67 mmol) of 2,3-dichlorobenzyl chloride, 40 mg (13 of theory) %).

LC-MS (Method 1): Rt = 0.94 min; m / z = 489 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.30 (s, partially hidden by water signal), 4.19 (q, 2H), 5.09 (s, 2H), 7.16-7.27 (m, 4H), 7.32 (t, 1H), 7.56-7.60 (m, 1H), 8.41. (S, 1H), 11.14 (s, 1H).

Example 16
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 1. The reaction time was 5 hours. 1- (1-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5 from Example 36A Starting from 200 mg (0.61 mmol) of ethyl carboxylate and 182 mg (0.67 mmol) of 2-chloro-3- (trifluoromethyl) benzyl bromide, after purification by preparative HPLC (Method 8) 33 mg of the title compound ( 10% of theory) was obtained.

LC-MS (Method 1): Rt = 0.97 min; m / z = 523 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.30 (s, partially hidden by water signal), 4.20 (q, 2H), 5.14 (s, 2H), 7.19-7.23 (m, 3H), 7.48-7.55 (m, 1H), 7.58-7.62 (m, 1H) , 7.78-7.82 (m, 1H), 8.42 (s, 1H), 11.14 (s, 1H).

Example 17
3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- (1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  1- (1-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5 from Example 36A -In a solution of 0.74 g (2.24 mmol) of ethyl carboxylate in DMF (28 mL), 1- (bromomethyl) -3-chloro-2- (trifluoromethyl) benzene (preparation: WO 2004/52858, p. 149, carried out) (See Example 176) 1.04 g (65% purity, 2.46 mmol), 0.62 g (4.48 mmol) potassium carbonate and 0.04 g (0.22 mmol) potassium iodide are added and the mixture is stirred at 60 ° C. for 5 hours. did. For workup, the reaction mixture was mixed with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (dichloromethane / methanol, 50: 1). This gave 0.36 g (29% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.96 min; MS (ESI cation): m / z = 523 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.3 (s, hidden by DMSO signal), 4.19 (q, 2H), 5 .18-5.24 (m, 2H), 7.16-7.23 (m, 3H), 7.33-7.38 (m, 1H), 7.55-7.67 (m, 2H) , 8.43 (s, 1H), 11.15 (s, 1H).

Example 18
3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2, 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  First, 3- [3-chloro-2- (trifluoromethyl) benzyl] -1- (1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl from Example 17 ) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 120 mg (0.23 mmol) was placed in DMF (3 mL), iodoethane 39 mg (0.25 mmol), potassium carbonate 63 mg (0.46 mmol) and 4 mg (0.02 mmol) of potassium iodide were added. The reaction mixture was stirred at 60 ° C. for 5 hours. The reaction mixture was cooled to room temperature and mixed with water, the precipitate was filtered off with suction, washed with water and MTBE and dried at 50 ° C. in vacuo. After further purification by flash chromatography (dichloromethane / methanol 70: 1), 73 mg (55% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.11 min; m / z = 551 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.19-1.26 (m, 6H), 3.37 (s, 3H), 3.87 (q, 2H), 4. 20 (q, 2H), 5.20-5.25 (m, 2H), 7.22-7.30 (m, 2H), 7.31-7.35 (m, 1H), 7.44- 7.46 (m, 1H), 7.57-7.67 (m, 2H), 8.47 (s, 1H).

Example 19
3- [2-chloro-3- (trifluoromethyl) benzyl] -1- (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2, 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 18. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2 from Example 16 Starting from 90 mg (0.17 mmol) of ethyl 1,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate and 29 mg (0.19 mmol) of iodoethane 75 mg (77% of theory) of the title compound Got.

LC-MS (Method 1): Rt = 1.11 min; m / z = 551 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.19-1.27 (m, 6H), 3.37 (s, partially hidden by water signal); 88 (q, 2H), 4.20 (q, 2H), 5.16 (s, 2H), 7.22-7.31 (m, 2H), 7.44-7.48 (m, 1H) 7.50-7.60 (m, 2H), 7.78-7.82 (m, 1H), 8.47 (s, 1H).

Example 20
1- (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2, 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 18. 1- (1-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2 from Example 14 Starting from 214 mg (0.42 mmol) of ethyl 1,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate and 73 mg (0.47 mmol) of iodoethane 152 mg (65% of theory) of the title compound Got.

LC-MS (Method 1): Rt = 1.06 min; m / z = 531 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.19-1.26 (m, 6H), 2.46 (s, partially hidden by DMSO signal); 37 (s, partially hidden by water signal), 3.87 (q, 2H), 4.20 (q, 2H), 5.09 (s, 2H), 7.23-7.30 (M, 2H), 7.33-7.39 (m, 2H), 7.47-7.49 (m, 1H), 7.59-7.62 (m, 1H), 8.44 (s) 1H).

Example 21
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 1. The reaction time was 5 hours. 1- (1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 22A Starting from 200 mg (0.54 mmol) of ethyl-5-carboxylate and 162 mg (0.59 mmol) of 2-chloro-3- (trifluoromethyl) benzyl bromide, 204 mg (66% of theory) of the title compound were obtained. .

LC-MS (Method 1): Rt = 1.17 min; m / z = 565 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.19-1.26 (m, 9H), 3.84-3.95 (m, 4H), 4.20 (q, 2H) ), 5.16 (s, 2H), 7.22-7.27 (m, 1H), 7.34 (d, 1H), 7.44-7.48 (m, 1H), 7.50- 7.60 (m, 2H), 7.78-7.83 (m, 1H), 8.48 (s, 1H).

Example 22
1- (1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 1. The reaction time was 5 hours. 1- (1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 22A Starting from 200 mg (0.54 mmol) of ethyl-5-carboxylate and 150 mg (0.59 mmol) of 2-methyl-3- (trifluoromethyl) benzyl bromide, 174 mg (59% of theory) of the title compound were obtained. .

LC-MS (Method 1): Rt = 1.16 min; m / z = 545 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (d, 9H), 2.46 (s, 3H), 3.83-3.95 (m, 4H), 4. 20 (q, 2H), 5.09 (s, 2H), 7.22-7.26 (m, 1H), 7.31-7.41 (m, 3H), 7.46-7.49 ( m, 1H), 7.58-7.62 (m, 1H), 8.46 (s, 1H).

Example 23
3- (2,3-Dichlorobenzyl) -1- (1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2, 3,4-Tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 1. The reaction time was 5 hours. 1- (1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 22A Starting from 200 mg (0.53 mmol) ethyl-5-carboxylate and 115 mg (0.59 mmol) 2,3-dichlorobenzyl chloride, 244 mg (81% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.15 min; m / z = 531 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.18-1.27 (m, 9H), 3.82-3.97 (m, 4H), 4.20 (q, 2H) ), 5.11 (s, 2H), 7.19-7.27 (m, 2H), 7.30-7.38 (m, 2H), 7.46 (d, 1H), 7.59 ( d, 1H), 8.47 (s, 1H).

Example 24
1- (1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [3-fluoro-2- (trifluoromethyl) benzyl] -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 1. The reaction time was 5 hours. 1- (1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 22A Starting from 165 mg (0.44 mmol) of ethyl-5-carboxylate and 125 mg (0.48 mmol) of 1- (bromomethyl) -3-fluoro-2- (trifluoromethyl) benzene, 198 mg (82 of theory) %).

LC-MS (Method 3): Rt = 1.28 min; m / z = 549 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (td, 9H), 3.82-3.96 (m, 4H), 4.20 (q, 2H), 5. 21 (s, 2H), 7.17-7.26 (m, 2H), 7.31-7.49 (m, 3H), 7.67 (q, 1H), 8.49 (s, 1H) .

Example 25
3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- [1-methyl-2-oxo-3- (2,2,2-trifluoroethyl) -2,3-dihydro-1H- Benzimidazol-5-yl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  First, 3- [3-chloro-2- (trifluoromethyl) benzyl] -1- (1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl from Example 17 ) 121 mg (0.23 mmol) of ethyl 2,2,2-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate in DMF (3 mL) and 2,2,2-trichloromethanesulfonic acid 76 μL of fluoroethyl (130 mg, 0.46 mmol), 64 mg (0.46 mmol) of potassium carbonate and 4 mg (0.02 mmol) of potassium iodide were added. The reaction mixture was stirred at 60 ° C. for 5 hours. The reaction mixture was cooled to room temperature and mixed with water, the precipitate was filtered off with suction, washed with water and MTBE and dried at 50 ° C. in vacuo. After further purification by flash chromatography (dichloromethane / methanol 70: 1), 91 mg (63% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.16 min; m / z = 605 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.41 (s, 3H), 4.20 (q, 2H), 4.80 (q, 2H), 5.22 (br.s, 2H), 7.31-7.39 (m, 3H), 7.53 (s, 1H), 7.57-7.67 (m, 2H), 8 .44 (s, 1H).

Example 26
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- [1-methyl-2-oxo-3- (2,2,2-trifluoroethyl) -2,3-dihydro-1H- Benzimidazol-5-yl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 25. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2 from Example 16 Starting from 89 mg (0.17 mmol) of ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate and 96 mg (0.34 mmol) of 2,2,2-trifluoroethyl trichloromethanesulfonate This gave 80 mg (75% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.16 min; m / z = 605 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.41 (s, 3H), 4.21 (q, 2H), 4.80 (q, 2H), 5.15 (s, 2H), 7.31-7.39 (m, 2H), 7.50-7.56 (m, 2H), 7.57-7.61 (m, 1H) 7.78-7.82 (m, 1H), 8.43 (s, 1H).

Example 27
1- [1-Methyl-2-oxo-3- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3- [2-methyl-3- (Trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 25. 1- (1-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2 from Example 14 , 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 133 mg (purity 75%, 0.19 mmol) and 2,2,2-trifluoroethyl trichloromethanesulfonate 111 mg (0.39 mmol) After purification by flash chromatography (dichloromethane / methanol 100: 1), 41 mg (35% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.15 min; m / z = 585 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 2.46 (s, 3H), 3.41 (s, 3H), 4.20 (q, 2H), 4.79 (q, 2H), 5.08 (s, 2H), 7.32-7.41 (m, 4H), 7.54-7.57 (m, 1H), 7.58. -7.63 (m, 1H), 8.41 (s, 1H).

Example 28
1- [1-Methyl-2-oxo-3- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-benzimidazol-5-yl] -2,4-dioxo-3- [ (1R) -4- (Trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer)

  First, 1- [1-methyl-2-oxo-3- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-benzimidazol-5-yl] -2 from Example 25A. , 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 400 mg (0.97 mmol), (1S) -4- (trifluoromethyl) indan-1-ol 235 mg from Example 14A (1.16 mmol) and 763 mg (2.91 mmol) of triphenylphosphine were placed in DMF / THF 1: 1 (19.6 mL) under argon, the reaction mixture was cooled to −15 ° C., and diisopropyl azodicarboxylate 0.8. Mixed with 53 mL (2.71 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then an additional 0.2 equivalents (38 μL, 0.19 mmol) of diisopropyl azodicarboxylate was added dropwise with ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ° C., mixed with 1N hydrochloric acid and stirred at room temperature for 15 minutes. The formed solution was extracted with ethyl acetate. The organic phase was washed successively with 1N hydrochloric acid twice, saturated sodium carbonate solution twice and saturated sodium chloride solution once, dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC (Method 7). This gave 370 mg (57% of theory) of the title compound.

LC-MS (Method 5) Rt = 1.17 min; m / z = 597 (M + H) ^<+> .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.23 (t, 3H), 2.29-2.42 (m, 1H), 2.43-2.57 (m, 1H ), 3.00-3.12 (m, 1H), 3.31-3.44 (m, 4H), 4.20 (q, 2H), 4.41 (q, 2H), 6.47- 6.60 (m, 1H), 6.94-7.07 (m, 3H), 7.17-7.28 (m, 2H), 7.41 (d, 1H), 8.22 (s, 1H).

Example 29
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- [3- (cyclopropylmethyl) -1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl ] -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2 from Example 16 , 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 90 mg (0.17 mmol) in DMF (2 mL) in a solution of (bromomethyl) cyclopropane 254 mg (0.18 mmol), potassium carbonate 47 mg And 3 mg of potassium iodide were added. The reaction mixture was then stirred at 60 ° C. for 5 hours. After cooling to room temperature, water was added and the resulting precipitate was filtered. The solid was washed sequentially with water and MTBE and vacuum dried at 50 ° C. The solid was dissolved in dichloromethane and purified by flash chromatography (dichloromethane / methanol 70/1). The resulting product was dried under high vacuum. This gave 67 mg (66% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.17 min; m / z = 577 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 0.34-0.50 (m, 4H), 1.14-1.26 (m, 4H), 3.38 (s, 3H), 3 .72 (d, 2H), 4.20 (q, 2H), 5.15 (s, 2H), 7.23-7.31 (m, 2H), 7.50-7.60 (m, 3H) ), 7.80 (d, 1H), 8.46 (s, 1H).

Example 30
1- [3- (Cyclopropylmethyl) -1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] -3- [2-methyl-3- (trifluoromethyl) benzyl ] -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 29. 1- (1-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2 from Example 14 Starting from 133 mg (75% purity, 0.19 mmol) of ethyl 1,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate and 29 mg (0.18 mmol) of (bromomethyl) cyclopropane 69 mg (56% of theory) were obtained.

LC-MS (Method 1): Rt = 1.16 min; m / z = 557 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.35 to 0.41 (m, 2H), 0.42 to 0.49 (m, 2H), 1.16 to 1.26 (M, 4H), 2.46 (s, 3H), 3.38 (s, 3H), 3.72 (d, 2H), 4.20 (q, 2H), 5.09 (s, 2H) , 7.23-7.30 (m, 2H), 7.33-7.40 (m, 2H), 7.52-7.54 (m, 1H), 7.59-7.62 (m, 1H), 8.44 (s, 1H).

Example 31
3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- [3- (cyclopropylmethyl) -1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl ] -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 29. 3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- (1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2 from Example 17 Starting from 120 mg (0.23 mmol) of ethyl 1,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate and 34 mg (0.25 mmol) of (bromomethyl) cyclopropane Of 62%).

LC-MS (Method 1): Rt = 1.17 min; m / z = 577 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.35-0.41 (m, 2H), 0.41-0.49 (m, 2H), 1.14-1.27 (M, 4H), 3.38 (s, 3H), 3.72 (d, 2H), 4.20 (q, 2H), 5.22 (br.s, 2H), 7.22-7. 30 (m, 2H), 7.31-7.36 (m, 1H), 7.49-7.52 (m, 1H), 7.57-7.67 (m, 2H), 8.47 ( s, 1H).

Example 32
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- [1-methyl-3- (oxetan-2-ylmethyl) -2-oxo-2,3-dihydro-1H-benzimidazole-5 -Yl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

  First, 3- [2-chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl from Example 16 ) 100 mg (0.23 mmol) of ethyl 2, -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate was added to 2.4 mL of DMF, and 32 mg (0.21 mmol) of 2- (bromomethyl) oxetane. ), 53 mg (0.38 mmol) of potassium carbonate and 3 mg (0.02 mmol) of potassium iodide. The reaction mixture was stirred at 60 ° C. for 2 hours. Then an additional 1 equivalent of 2- (bromomethyl) oxetane was added at room temperature and the reaction mixture was stirred at 80 ° C. for 2 hours. For workup, the reaction mixture was mixed with water and the precipitate was filtered off with suction, washed with water and dried at 50 ° C. in vacuo. The solid was dissolved in dichloromethane and purified by flash silica gel chromatography (dichloromethane / methanol 70: 1). This gave 56 mg (50% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.09 min; m / z = 593 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 1.23 (t, 3H), 2.10-2.22 (m, 1H), 2.25-2.38 (m, 1H), 3 .36 (s, 3H), 3.39-3.48 (m, 1H), 3.73 (q, 1H), 3.85-3.92 (m, 1H), 3.92-3.98 (M, 1H), 4.11-4.17 (m, 1H), 4.21 (q, 2H), 5.15 (s, 2H), 7.25-7.33 (m, 2H), 7.45 (s, 1H), 7.53 (t, 1H), 7.60 (d, 1H), 7.80 (d, 1H), 8.46 (s, 1H).

Example 33
1- (3-cyclobutyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2, 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  First, 39 μL (0.49 mmol) of cyclobutanol and 130 mg (0.49 mmol) of triphenylphosphine were placed in THF (2.5 mL) under argon, and 98 μL (0.49 mmol) of diisopropyl azodicarboxylate was slowly added dropwise. 1- (1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl]-from Example 14. 100 mg (0.19 mmol) of ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated and purified by preparative HPLC (Method 8). This gave 46 mg (41% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.16 min; m / z = 557 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.72-1.91 (m, 2H), 2.20-2.30 (m, 2H) ), 2.47 (s, partially hidden by DMSO signal), 2.75-2.87 (m, 2H), 3.31 (s, partially hidden by water signal) 4.20 (q, 2H), 4.78-4.88 (m, 1H), 5.09 (s, 2H), 7.24-7.29 (m, 2H), 7.33-7 .42 (m, 2H), 7.60 (d, 1H), 7.67 (s, 1H), 8.45 (s, 1H).

Example 34
1- (3-Isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2, 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 33. 1- (1-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2 from Example 14 , 4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 100 mg (0.19 mmol) and 2-propanol 38 μL (0.49 mmol) by preparative HPLC (Method 8) After further purification, 38 mg (34% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.12 min; m / z = 545 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.45 (d, 6H), 2.46 (s, partially hidden by the DMSO signal 3.31 (s, partially hidden by water signal), 4.20 (q, 2H), 4.54-4.65 (m, 1H), 5.09 (s, 2H) ), 7.22-7.29 (m, 2H), 7.32-7.41 (m, 2H), 7.58-7.62 (m, 2H), 8.43 (s, 1H).

Example 35
1- (3-Cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2 , 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  First, 1- (1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl from Example 14 ] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 250 mg (0.49 mmol), cyclopropylboronic acid 85 mg (0.99 mmol) and triethylamine 0.41 mL (2.98 mmol) ) Was taken up in dichloromethane (4 mL). Molecular sieves (3Å) and 271 mg (1.49 mmol) copper (II) acetate were added and the reaction mixture was stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate and washed twice with 1M hydrochloric acid, once with saturated sodium bicarbonate solution, and once with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 8). This gave 155 mg (56% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.06 min; m / z = 543 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.86-0.92 (m, 2H), 0.99-1.06 (m, 2H), 1.23 (t, 3H ), 2.46 (s, partially obscured by DMSO signal), 2.87-2.95 (m, 1H), 3.31 (s, partially obscured by water signal) 4.20 (q, 2H), 5.08 (s, 2H), 7.22-7.28 (m, 2H), 7.32-7.43 (m, 2H), 7.47 (s) 1H), 7.60 (d, 1H), 8.41 (s, 1H).

Example 36
1- (3-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) -benzyl] -2,4-dioxo -1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  1- (3-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5 from Example 34A -In a solution of 250 mg (0.76 mmol) of ethyl carboxylate in DMF (10 mL), 211 mg (0.83 mmol) of 1- (bromomethyl) -2-methyl-3- (trifluoromethyl) benzene, 209 mg of potassium carbonate (1. 51 mmol) and 13 mg (0.08 mmol) potassium iodide were added and the mixture was stirred at 60 ° C. for 3 h. For workup, the reaction mixture was mixed with water and the resulting precipitate was filtered off with suction, washed with water and MTBE and dried at 50 ° C. under high vacuum overnight. This gave 42 mg (11% of theory) of the target compound.

LC-MS (Method 3): Rt = 1.19 min; MS (ESI cation): m / z = 503 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 3.41 (s, 3H), 4.17 (q, 2H), 5.20 (s, 2H), 7.07-7.16 (m, 3H), 7.29-7.36 (m, 1H), 7.46 (s, 1H), 7.62 (d, 1H), 8.28. (S, 1H), 11.70 (s, 1H).

Example 37
3- [2-Chloro-3- (trifluoromethyl) benzyl] -2,4-dioxo-1- (2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -1,2, 3,4-Tetrahydropyrimidine-5-carboxylate ethyl

  First, 2,4-dioxo-1- (2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -1,2,3,4-tetrahydropyrimidine-5 from Example 26A. 200 mg (0.63 mmol) of ethyl carboxylate was placed in 8 mL of DMF. 190 mg (0.70 mmol) of 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene, 175 mg (1.27 mmol) of potassium carbonate and 10.5 mg (63 μmol) of potassium iodide are added and the reaction mixture is added to 60 Stir at 5 ° C. for 5 hours. After cooling to room temperature, water was added to the mixture. The precipitate was filtered, washed with a small amount of water and MTBE and dried at 50 ° C. in a drying cabinet. The resulting product was dissolved in a small amount of DMF and purified by preparative HPLC (Method 8). This gave 111 mg (35% of theory) of the title compound.

LC-MS (Method 3): Rt = 1.13 min; m / z = 509 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 4.20 (q, 2H), 5.14 (s, 2H), 7.02 (d, 1H), 7.09 (dd, 1H), 7.15 (s, 1H), 7.51 (t, 1H), 7.59 (d, 1H), 7.79 (d, 1H), 8. 41 (s, 1H), 10.88 (d, 2H).

Example 38
1- [3-Methyl-2-oxo-1- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3- [2-methyl-3- (Trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 25. 1- (3-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2 from Example 36 Starting from 91 mg (0.18 mmol) of ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate and 101 mg (0.36 mmol) of 2,2,2-trifluoroethyl trichloromethanesulfonate To give 57 mg (52% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.11 min; m / z = 585 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 2.46 (s, 3H), 3.38 (s, 3H), 4.19 (q, 2H), 4.86 (q, 2H), 5.09 (s, 2H), 7.28-7.41 (m, 3H), 7.44 (d, 1H), 7.50 (d, 1H) ), 7.61 (d, 1H), 8.47 (s, 1H).

Example 39
1- [1- (Cyclopropylmethyl) -3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] -3- [2-methyl-3- (trifluoromethyl) benzyl ] -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  1- (3-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2 from Example 36 , 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 91 mg (0.18 mmol) was reacted with 26 mg (0.19 mmol) of (bromomethyl) cyclopropane in the same manner as in Example 29. It was. After a reaction time of 2 hours, an additional 24 mg (0.17 mmol) of (bromomethyl) cyclopropane was added and the reaction mixture was stirred at 80 ° C. for a further hour. The product was precipitated by adding water and filtered. After further purification by flash chromatography (dichloromethane / methanol 70: 1), 51 mg (51% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.13 min; m / z = 557 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 0.36-0.42 (m, 2H), 0.42-0.50 (m, 2H), 1.14-1.20 (m, 1H), 1.23 (t, 3H), 2.46 (s, 3H), 3.35 (s, 3H), 3.77 (d, 2H), 4.19 (q, 2H), 5. 09 (s, 2H), 7.24 (dd, 1H), 7.32-7.44 (m, 4H), 7.58-7.62 (m, 1H), 8.45 (s, 1H) .

Example 40
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The reaction time was 2 hours, and the title compound was produced and purified in the same manner as in Example 1. 1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 28A Starting from 200 mg (0.60 mmol) of ethyl-5-carboxylate and 168 mg (0.66 mmol) of 1- (bromomethyl) -2-methyl-3- (trifluoromethyl) benzene, 288 mg (93 of theory) %).

LC-MS (Method 5): Rt = 1.10 min; m / z = 504 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 2.46 (s, 3H), 3.38 (s, 3H), 4.20 (q, 2H), 5.07 (s, 2H), 7.31-7.42 (m, 3H), 7.43-7.48 (m, 1H), 7.58-7.62 (m, 1H) , 7.63-7.66 (m, 1H), 8.44 (s, 1H).

Example 41
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 1. The reaction time was 2 hours. 1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 28A Starting from 200 mg (0.60 mmol) of ethyl-5-carboxylate and 181 mg (0.66 mmol) of 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene, 263 mg (79 of theory) %).

LC-MS (Method 5): Rt = 1.11 min; m / z = 523 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 1.23 (t, 3H), 3.38 (s, 3H), 4.20 (q, 2H), 5.14 (s, 2H), 7.38-7.48 (m, 2H), 7.53 (t, 1H), 7.59 (d, 1H), 7.64 (s, 1H), 7.80 (d, 1H), 8 .47 (s, 1H).

Example 42
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-3-[(1R) -4- (trifluoromethyl)- 2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer)

  Method A: 1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2 from Example 28A under argon , 3,4-tetrahydropyrimidine-5-carboxylate 200 mg (0.60 mmol) and triphenylphosphine 475 mg (1.81 mmol) in THF / DMF 1: 1 (7.6 mL) was cooled to −30 ° C. did. 238 μL (1.20 mmol) diisopropyl azodicarboxylate was added dropwise followed by 146 mg (0.69 mmol) of (1S) -4- (trifluoromethyl) indan-1-ol from Example 14A in THF (ca. 1 mL). The solution was added dropwise. The reaction mixture was warmed to room temperature and stirred at room temperature for 30 minutes. For workup, the mixture was cooled to 0 ° C., mixed with 5 mL of 1M hydrochloric acid, warmed to room temperature and stirred for 30 minutes. The mixture was extracted with ethyl acetate. The organic phase was washed twice with 1M hydrochloric acid and once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was extracted and stirred with ethanol and the precipitated solid was filtered off with suction and discarded. The filtrate was concentrated, dissolved in a small amount of dichloromethane and purified by flash chromatography (dichloromethane / methanol 120: 1 to 20: 1). This gave 135 mg (43% of theory) of the title compound with a purity of about 95%.

LC-MS (Method 1): Rt = 1.13 min; m / z = 516 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 2.37-2.43 (m, 1H), 2.43-2.48 (m, 1H) , Partially hidden by DMSO signal), 3.03-3.14 (m, 1H), 3.22-3.30 (m, 1H, partly hidden by water signal), 3.38 (s, 3H), 4.18 (q, 2H), 6.34-6.56 (m, 1H), 7.32-7.43 (m, 3H), 7.45-7. 50 (m, 1H), 7.53 (d, 1H), 7.55-7.64 (m, 1H), 8.35 (s, 1H).

  In a similar experiment, it was possible to isolate a 99% pure fraction. For this batch, the measured specific rotations were as follows:

Specific rotation: α _D ²⁰ = + 132.9 °, (chloroform, c = 0.395 g / 100 mL).

  Method B: First, 1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2,3 from the examples. , 4-tetrahydropyrimidine-5-carboxylate 5.0 g (15.1 mmol), 6.73 g (25.7 mmol) triphenylphosphine and (1S) -4- (trifluoromethyl) indane- from Example 14A A solution of 1.66 g (18.1 mmol) of 1-ol was placed in 240 mL of DMF / THF 2: 1 (volume ratio) under argon and cooled to −15 ° C. 4.76 mL (24.15 mmol) of diisopropyl azodicarboxylate was slowly added dropwise at such a rate that the temperature of the reaction mixture did not rise above -10 ° C. After the addition was complete, the mixture was stirred at -10 ° C for an additional hour, then warmed to room temperature and poured into 1.3 liters of water. The mixture was extracted twice with 300 mL of ethyl acetate each time. The combined organic phases were washed with saturated sodium chloride solution, dehydrated with magnesium sulfate and the solvent was removed on a rotary evaporator. The residue (18g) was purified in two chromatographic steps. Initially, a 200 g silica gel column was used with dichloromethane / acetone 97.5: 2.5 as the eluent. The fraction containing the obtained product was concentrated, and the residue was loaded again on a 200 g silica gel column. Further impurities were eluted using 2.5 liters of cyclohexane / ethyl acetate 1: 1 as eluent, then the desired product was eluted from the column with dichloromethane / methanol 95: 5. This gave 3.40 g (44% of theory) of the title compound with a purity of 95% (NMR showed about 5% ethyl acetate). An additional 920 mg could be obtained by fresh purification of the mixed fraction. Overall yield: 4.32 g (56% of theory).

LC-MS (Method 1): Rt = 1.15 min; m / z = 516 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.31 (t, 3H), 2.37-2.49 (m, 1H), 2.59 (dtd, 1H), 3. 14 (dt, 1H), 3.40 (s, 3H), 3.42-3.53 (m, 1H), 4.29 (q, 2H), 6.54-6.68 (m, 1H) 7.06 (d, 1H), 7.17 (d, 1H), 7.22 (s, 1H), 7.26-7.36 (m, 2H), 7.49 (d, 1H), 8.28 (s, 1H).

Example 43
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-3-[(1S) -4- (trifluoromethyl)- 2,3-Dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (S enantiomer)

  First, 1.00 g (3.02 mmol) of the compound from Example 28A, 732 mg (3.62 mmol) of the compound from Example 15A and 1.35 g (5.13 mmol) of triphenylphosphine in 9 mL of THF and 18 mL of DMF. Then, 951 μL (4.83 mmol) of diisopropyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour. For workup, 5 mL of 1N hydrochloric acid was added to the reaction mixture with ice cooling, and the mixture was stirred for 10 minutes. The mixture was extracted with ethyl acetate. The combined organic phases were washed twice with 1N hydrochloric acid, twice with 1M sodium carbonate solution and once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (Method 15). This gave 590 mg (38% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.08 min; m / z = 516 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.31 (t, 3H), 2.33-3.50 (m, 1H), 2.51-2.67 (m, 1H ), 3.14 (dt, 1H), 3.39-3.52 (m, 1H), 3.40 (s, 3H), 4.29 (q, 2H), 6.55-6.68 ( m, 1H), 7.06 (d, 1H), 7.18 (d, 1H), 7.22 (s, 1H), 7.26-7.35 (m, 2H), 7.49 (d 1H), 8.28 (s, 1H).

  Chiral analytical HPLC (Method 27): Rt = 9.94 min; ca. 93% ee.

Example 44
1- (3-Ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 1. The reaction time was 5 hours. 1- (3-Ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 30A Starting from 200 mg (0.58 mmol) of ethyl-5-carboxylate and 161 mg (0.64 mmol) of 2-methyl-3- (trifluoromethyl) benzyl bromide, 192 mg (64% of theory) of the title compound were obtained. .

LC-MS (Method 1): Rt = 1.11 min; m / z = 518 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.28 (t, 3H), 2.46 (s, 3H), 3.90 (q, 2H), 4.20 (q, 2H), 5.08 (s, 2H), 7.31-7.42 (m, 2H), 7.43-7.50 (m, 2H), 7.58 -7.62 (m, 1H), 7.64-7.67 (m, 1H), 8.45 (s, 1H).

Example 45
3- (2,3-dichlorobenzyl) -1- (3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2, 3,4-Tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 1. The reaction time was 5 hours. 1- (3-Ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 30A Starting from 200 mg (0.58 mmol) of ethyl 5-carboxylate and 124 mg (0.64 mmol) of 1,2-dichloro-3- (chloromethyl) benzene, 220 mg (75% of theory) of the title compound were obtained. .

LC-MS (Method 1): Rt = 1.09 min; m / z = 504 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.28 (t, 3H), 3.90 (q, 2H), 4.20 (q, 2H), 5.10 (s, 2H), 7.21-7.25 (m, 1H), 7.30-7.36 (m, 1H), 7.41-7.50 (m, 2H) 7.56-7.60 (m, 1H), 7.63-7.66 (m, 1H), 8.47 (s, 1H).

Example 46
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 37. 1- (3-Ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 30A Starting from 200 mg (0.58 mmol) of ethyl-5-carboxylate and 174 mg (0.63 mmol) of 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene, 209 mg (67% of theory) %).

LC-MS (Method 1): Rt = 1.11 min; m / z = 538 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.28 (t, 3H), 3.90 (q, 2H), 4.20 (q, 2H), 5.14 (s, 2H), 7.42-7.56 (m, 3H), 7.59 (d, 1H), 7.65 (d, 1H), 7.81 (d, 1H) ), 8.48 (s, 1H).

Example 47
1- (3-Ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -3- [3-fluoro-2- (trifluoromethyl) benzyl] -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 37. 1- (3-Ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 30A Starting from 200 mg (0.58 mmol) of ethyl-5-carboxylate and 163 mg (0.63 mmol) of 1- (bromomethyl) -3-fluoro-2- (trifluoromethyl) benzene, 159 mg (52 of theory) %).

LC-MS (Method 1): Rt = 1.06 min; m / z = 522 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.28 (t, 3H), 3.90 (q, 2H), 4.20 (q, 2H), 5.19 (s, 2H), 7.18-7.23 (m, 1H), 7.37-7.51 (m, 3H), 7.62-7.70 (m, 2H) 8.49 (s, 1H).

Example 48
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -3- [2-methyl-3- (trifluoromethyl) -benzyl] -2,4 -Ethyl dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 37. 1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 31A Starting from 500 mg (1.44 mmol) of ethyl-5-carboxylate and 400 mg (1.58 mmol) of 1- (bromomethyl) -2-methyl-3- (trifluoromethyl) benzene, 392 mg (50 of theoretical amount) %).

LC-MS (Method 3): Rt = 1.11 min; m / z = 520 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 2.46 (s, partially hidden by the DMSO signal), 3.45 (s, 3H), 4.20 (q, 2H), 5.08 (s, 2H), 7.31-7.42 (m, 2H), 7.46 (d, 1H), 7.56-7.63 (M, 2H), 7.88-7.91 (m, 1H), 8.48 (s, 1H).

Example 49
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 37. 1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 31A Starting from 184 mg (0.53 mmol) of ethyl-5-carboxylate and 159 mg (0.58 mmol) of 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene, 216 mg (75 of theory) %).

LC-MS (Method 1): Rt = 1.11 min; m / z = 540 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (t, 3H), 3.45 (s, 3H), 4.20 (q, 2H), 5.15 (s, 2H), 7.46 (d, 1H), 7.49-7.55 (m, 1H), 7.56-7.61 (m, 2H), 7.78-7.82 (m, 1H) 7.88-7.90 (m, 1H), 8.51 (s, 1H).

Example 50
3- [3-Fluoro-2- (trifluoromethyl) benzyl] -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 37. 1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 31A Starting from 200 mg (0.53 mmol) of ethyl-5-carboxylate and 149 mg (0.58 mmol) of 1- (bromomethyl) -3-fluoro-2- (trifluoromethyl) benzene, 241 mg (87 of theory) %).

LC-MS (Method 1): Rt = 1.06 min; m / z = 524 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.45 (s, 3H), 4.20 (q, 2H), 5.19 (s, 2H), 7.21 (d, 1H), 7.41 (t, 1H), 7.47 (d, 1H), 7.57 (dd, 1H), 7.66 (q, 1H), 7. 88 (d, 1H), 8.52 (s, 1H).

Example 51
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-3-[(1R) -4- (trifluoromethyl)- 2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer)

  First, 1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-1,2,3,4 from Example 31A. -8.00 g (23.03 mmol) of ethyl tetrahydropyrimidine-5-carboxylate, 5.12 g (25.33 mmol) of (1S) -4- (trifluoromethyl) indan-1-ol from Example 14A and triphenyl Phosphine 10.27 g (39.15 mmol) was placed in THF 317 mL and DMF 317 mL and cooled to 5 ° C. 7.25 mL (36.85 mmol) diisopropyl azodicarboxylate was added in small portions. The cooling bath was removed and the mixture was stirred at room temperature for 1 hour. For workup, 200 mL of 1N hydrochloric acid was added and the mixture was stirred vigorously for 5 minutes. 400 mL of ethyl acetate was added. After high stirring for 10 minutes, the organic phase was removed. The aqueous phase was extracted once more with 400 mL of ethyl acetate. The combined organic phases were washed twice with 100 mL each time of saturated sodium carbonate solution, then with 100 mL saturated sodium chloride solution, then dried over sodium sulfate and concentrated on a rotary evaporator. The residue was mixed with 400 mL MTBE and stirred for 30 minutes while cooling with an ice bath. The precipitated solid was filtered off with suction and washed twice with cold MTBE. The combined filtrate was concentrated and the residue was purified by flash chromatography (cyclohexane / ethyl acetate 1: 2 to 1: 4). The product so obtained was recrystallized from acetonitrile and dried under high vacuum. This gave 6.3 g (50% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.18 min; m / z = 532 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.31 (t, 3H), 2.37-2.49 (m, 1H), 2.53-2.65 (m, 1H) ), 3.08-3.20 (m, 1H), 3.40-3.52 (m, 1H), 3.45 (s, 3H), 4.29 (q, 2H), 6.56- 6.68 (m, 1H), 7.09-7.18 (m, 1H), 7.25-7.36 (m, 3H), 7.44 (s, 1H), 7.47-7. 54 (m, 1H), 8.29 (s, 1H).

Example 52
3- [2-Chloro-3- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indole-5 Yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 37. 2,4-Dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -1,2,3,4-tetrahydro from Example 59A Starting from 200 mg (0.56 mmol) of ethyl pyrimidine-5-carboxylate and 168 mg (0.61 mmol) of 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene, 241 mg (theoretical amount) of the title compound 77%).

LC-MS (Method 1): Rt = 1.11 min; m / z = 550 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (t, 3H), 1.30 (s, 6H), 3.18 (s, 3H), 4.21 (q, 2H), 5.15 (s, 2H), 7.16 (d, 1H), 7.44-7.49 (m, 1H), 7.50-7.60 (m, 3H), 7.78. -7.83 (m, 1H), 8.44 (s, 1H).

Example 53
3- [2-Methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indole-5 Yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 37. 2,4-Dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -1,2,3,4-tetrahydro from Example 59A Starting from 500 mg (1.39 mmol) of ethyl pyrimidine-5-carboxylate and 389 mg (1.53 mmol) of 1- (bromomethyl) -2-methyl-3- (trifluoromethyl) benzene, 571 mg (theoretical amount of the title compound) 77%).

LC-MS (Method 1): Rt = 1.11 min; m / z = 530 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.29 (s, 6H), 2.46 (s, 3H), 3.18 (s, 3H), 3.30 (s, 3H), 4.20 (q, 2H), 5.08 (s, 2H), 7.15 (d, 1H), 7.34-7.39 (m, 2H), 7.44-7.49. (M, 1H), 7.53-7.56 (m, 1H), 7.58-7.63 (m, 1H), 8.42 (s, 1H).

Example 54
3- [3-Chloro-2- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indole-5 Yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  Analogously to Example 37, 2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -1 from Example 59A , 2,3,4-Tetrahydropyrimidine-5-carboxylate 153 mg (0.42 mmol) 1- (bromomethyl) -3-chloro-2- (trifluoromethyl) benzene (preparation: WO 2004/52858, p. 149, Reaction with 198 mg (65% purity, 0.47 mmol). For workup, the reaction mixture cooled to room temperature was mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue was stirred with MTBE, the precipitated solid was filtered off with suction, washed with MTBE and dried with a high vacuum pump. This gave 109 mg (46% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.14 min; m / z = 550 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.29 (s, 6H), 3.18 (s, 3H), 4.20 (q, 2H), 5.21 (br.s, 2H), 7.16 (d, 1H), 7.30-7.35 (m, 1H), 7.45 (dd, 1H), 7.53 (d 1H), 7.57-7.66 (m, 2H), 8.45 (s, 1H).

Example 55
3- [3-Fluoro-2- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indole-5 Yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 37. 2,4-Dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -1,2,3,4-tetrahydro from Example 59A Starting from 200 mg (0.56 mmol) of ethyl pyrimidine-5-carboxylate and 158 mg (0.61 mmol) of 1- (bromomethyl) -3-fluoro-2- (trifluoromethyl) benzene, 247 mg (theoretical amount of the title compound) 80%).

LC-MS (Method 1): Rt = 1.06 min; m / z = 534 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.29 (s, 6H), 3.18 (s, 3H), 4.20 (q, 2H), 5.20 (s, 2H), 7.13-7.22 (m, 2H), 7.37-7.48 (m, 2H), 7.53 (d, 1H), 7.63. -7.70 (m, 1H), 8.45 (s, 1H).

Example 56
3- (2,3-Dichlorobenzyl) -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -1,2 , 3,4-Tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 37. 2,4-Dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -1,2,3,4-tetrahydro from Example 59A Starting from 200 mg (0.56 mmol) of ethyl pyrimidine-5-carboxylate and 120 mg (0.61 mmol) of 1,2-dichloro-3- (chloromethyl) benzene, 230 mg (78% of theory) of the title compound are obtained. It was.

LC-MS (Method 1): Rt = 1.09 min; m / z = 520 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.29 (s, 6H), 3.18 (s, 3H), 4.20 (q, 2H), 7.15 (d, 1H), 7.22 (d, 1H), 7.33 (t, 1H), 7.46 (dd, 1H), 7.54 (d, 1H), 7. 58 (d, 1H), 8.43 (s, 1H).

Example 57
2,4-Dioxo-3- [4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1- (1,3,3-trimethyl-2-oxo-2,3 -Dihydro-1H-indol-5-yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

  The title compound was prepared and purified as in Example 8. The reaction time was 2 days. 2,4-Dioxo-3- [4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5 from Example 21A 190 mg (0.51 mmol) of ethyl carboxylate and 1,3,3-trimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-from Example 68A After further purification by flash chromatography (dichloromethane / methanol 98: 2) starting from 310 mg (1.03 mmol) of 1,3-dihydro-2H-indol-2-one, a total of 169 mg (60% of theory) of the title compound was obtained. %).

LC-MS (Method 1): Rt = 1.14 min; m / z = 542 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.20-1.25 (m, 3H), 1.29 (s, 6H), 2.38-2.43 (m, 1H) ), 2.44-2.48 (m, 1H, partially hidden by the DMSO signal), 3.03-3.13 (m, 1H), 3.17 (s, 3H), 3. 23-3.29 (m, 1H, partially hidden by water signal), 4.18 (q, 2H), 6.33-6.56 (m, 1H), 7.13 (d, 1H), 7.32-7.45 (m, 2H), 7.45-7.57 (m, 3H), 8.33 (s, 1H).

Example 58
2,4-Dioxo-3- [4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1- (1,3,3-trimethyl-2-oxo-2,3 -Dihydro-1H-indol-5-yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer)

  700 mg (1.96 mmol) of the compound from Example 59A, 515 mg (2.55 mmol) of (S) -4-trifluoromethylindan-1-ol from Example 14A and 1.54 g (5.88 mmol) of triphenylphosphine. Was first added to 20 mL of THF and 20 mL of DMF at −15 ° C., and 1.12 mL (5.68 mmol) of diisopropyl azodicarboxylate was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. For workup, the mixture was cooled again to −15 ° C., mixed with 30 mL of 1N hydrochloric acid, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. The organic phase was washed twice with 1N hydrochloric acid, once with 1M sodium carbonate solution and once with saturated sodium chloride solution, then dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (Method 7). This gave 725 mg (68% of theory) of the title compound.

LC-MS (Method 5): Rt = 1.18 min; m / z = 542 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.31 (t, 3H), 1.35 (s, 3H), 1.36 (s, 3H), 2.37-2. 50 (m, 1H), 2.58 (dtd, 1H), 3.08-3.18 (m, 1H), 3.20 (s, 3H), 3.47 (br.s, 1H), 4 .29 (q, 2H), 6.54-6.68 (m, 1H), 6.92 (d, 1H), 7.16 (br.s, 1H), 7.21 (d, 1H), 7.26-7.36 (m, 2H), 7.49 (d, 1H), 8.29 (s, 1H).

Example 59
3- [2-Methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indole-6 Yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  First, 2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -1,2,3 from Example 64A. 125 mg (0.35 mmol) of ethyl 4-tetrahydropyrimidine-5-carboxylate was placed in 3 mL of DMF. 97 mg (0.38 mmol) of 1- (bromomethyl) -2-methyl-3- (trifluoromethyl) benzene, 97 mg (0.70 mmol) of potassium carbonate and 6 mg (0.04 mmol) of potassium iodide were added, and the reaction mixture was added to 60 Stir at 0 ° C. for 2 hours. After cooling to room temperature, water was added to the mixture. The precipitate was filtered, washed with a small amount of water and cyclohexane, and dried at 50 ° C. in a drying cabinet. This gave 134 mg (purity 90%, 65% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.16 min; m / z = 530 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (t, 3H), 1.30 (s, 6H), 2.47 (s, 3H), 3.14 (s, 3H), 4.20 (q, 2H), 5.09 (s, 2H), 7.22 (dd, 1H), 7.27 (d, 1H), 7.31-7.41 (m, 2H) ), 7.51 (d, 1H), 7.60 (d, 1H), 8.47 (s, 1H).

Example 60
3- [2-Chloro-3- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indole-6 Yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 59. 2,4-Dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -1,2,3,4-tetrahydro from Example 64A Starting from 125 mg (0.35 mmol) of ethyl pyrimidine-5-carboxylate and 105 mg (0.38 mmol) of 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene, 182 mg of the title compound (theoretical amount) 85%).

LC-MS (Method 1): Rt = 1.16 min; m / z = 550 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (t, 3H), 1.31 (s, 6H), 3.15 (s, 3H), 4.20 (q, 2H), 5.16 (s, 2H), 7.22 (dd, 1H), 7.26 (d, 1H), 7.50-7.55 (m, 2H), 7.58 (d, 1H) ), 7.80 (d, 1H), 8.49 (s, 1H).

Example 61
3- [3-Chloro-2- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indole-6 Yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  First, 2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -1,2,3 from Example 64A. 125 mg (0.35 mmol) of ethyl 4-tetrahydropyrimidine-5-carboxylate was placed in DMF (3 mL). 161 mg (purity 65%, 0.38 mmol) of 1- (bromomethyl) -3-chloro-2- (trifluoromethyl) benzene, 96 mg (0.70 mmol) of potassium carbonate and 6 mg (0.03 mmol) of potassium iodide were added. . The reaction mixture was then stirred at 60 ° C. for 2 hours. The mixture cooled to room temperature was mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue was stirred with cyclohexane / ethyl acetate and the precipitated solid was filtered off with suction and dried in vacuo. This gave 133 mg (62% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.16 min; m / z = 550 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (t, 3H), 1.30 (s, 6H), 3.15 (s, 3H), 4.20 (q, 2H), 5.22 (br.s, 2H), 7.21 (d, 1H), 7.25 (s, 1H), 7.33 (d, 1H), 7.51 (d, 1H), 7.56-7.68 (m, 2H), 8.50 (s, 1H).

Example 62
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (3-hydroxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2 , 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

  The title compound was prepared and purified as in Example 1. The reaction time was 1 hour. 1- (3-Hydroxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2,4-dioxo-1,2,3,4 from Example 72A Starting from 105 mg (0.29 mmol) of ethyl tetrahydropyrimidine-5-carboxylate and 88 mg (0.32 mmol) of 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene 133 mg (theoretical) 74% of the amount).

LC-MS (Method 1): Rt = 0.98 min; m / z = 552 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.41 (s, 3H), 3.14 (s, 3H), 4.21 (q, 2H), 5.14 (s, 2H), 6.13 (s, 1H), 7.14 (d, 1H), 7.47-7.57 (m, 3H), 7.58-7.62. (M, 1H), 7.78-7.82 (m, 1H), 8.40 (s, 1H).

Example 63
1- [3-Hydroxy-1-methyl-2-oxo-3- (trifluoromethyl) -2,3-dihydro-1H-indol-5-yl] -3- [2-methyl-3- (trifluoro Methyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

  The title compound was prepared and purified as in Example 1. The reaction time was 45 minutes. 1- [3-Hydroxy-1-methyl-2-oxo-3- (trifluoromethyl) -2,3-dihydro-1H-indol-5-yl] -2,4-dioxo-1 from Example 69A Starting from 200 mg (0.48 mmol) of ethyl 2,2,3,4-tetrahydropyrimidine-5-carboxylate and 134 mg (0.53 mmol) of 1- (bromomethyl) -2-methyl-3- (trifluoromethyl) benzene After further purification by HPLC (Method 8), 76 mg (26% of theory) of the title compound were obtained.

LC-MS (Method 5): Rt = 1.11 min; m / z = 585 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (t, 3H), 2.46 (s, 3H), 3.22 (s, 3H), 4.21 (q, 2H), 5.07 (s, 2H), 7.30 (d, 1H), 7.35 (t, 1H), 7.41 (d, 1H), 7.60 (d, 1H), 7. 67-7.71 (m, 1H), 7.73 (s, 1H), 7.92 (s, 1H), 8.40 (s, 1H).

Example 64
1- [3-Fluoro-1-methyl-2-oxo-3- (trifluoromethyl) -2,3-dihydro-1H-indol-5-yl] -3- [2-methyl-3- (trifluoro Methyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

  The title compound was prepared and purified as in Example 1. The reaction time was 45 minutes. 1- [3-Fluoro-1-methyl-2-oxo-3- (trifluoromethyl) -2,3-dihydro-1H-indol-5-yl] -2,4-dioxo-1 from Example 73A Starting from 90 mg (0.21 mmol) of ethyl 2,2,3,4-tetrahydropyrimidine-5-carboxylate and 60 mg (0.23 mmol) of 1- (bromomethyl) -2-methyl-3- (trifluoromethyl) benzene After further purification by HPLC (Method 8), 97 mg (72% of theory) of the title compound were obtained.

LC-MS (Method 5): Rt = 1.24 min; m / z = 588 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (t, 3H), 2.46 (s, 3H), 3.27 (s, 3H), 4.21 (q, 2H), 5.07 (s, 2H), 7.32-7.37 (m, 1H), 7.38-7.45 (m, 2H), 7.60 (d, 1H), 7.84 -7.88 (m, 1H), 7.96 (s, 1H), 8.53 (s, 1H).

Example 65
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1′-methyl-2′-oxo-1 ′, 2′-dihydrospiro [cyclopropane-1,3′-indole]- 5'-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 1. The reaction time was 1 hour. 1- (1′-Methyl-2′-oxo-1 ′, 2′-dihydrospiro [cyclopropane-1,3′-indole] -5′-yl) -2,4-dioxo- from Example 63A Starting from 120 mg (0.33 mmol) of ethyl 1,2,3,4-tetrahydropyrimidine-5-carboxylate and 101 mg (0.37 mmol) of 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene To give 177 mg (90% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.12 min; m / z = 548 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.55-1.60 (m, 2H), 1.64-1.69 (m, 2H) ), 3.26 (s, 3H), 4.20 (q, 2H), 5.14 (s, 2H), 7.18-7.24 (m, 2H), 7.44 (dd, 1H) 7.49-7.58 (m, 2H), 7.78-7.82 (m, 1H), 8.44 (s, 1H).

Example 66
1- (1′-methyl-2′-oxo-1 ′, 2′-dihydrospiro [cyclopropane-1,3′-indole] -5′-yl) -3- [2-methyl-3- (tri Fluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 1. The reaction time was 1.5 hours. 1- (1′-Methyl-2′-oxo-1 ′, 2′-dihydrospiro [cyclopropane-1,3′-indole] -5′-yl) -2,4-dioxo- from Example 63A Starting from 120 mg (0.33 mmol) of ethyl 1,2,3,4-tetrahydropyrimidine-5-carboxylate and 94 mg (0.37 mmol) of 1- (bromomethyl) -2-methyl-3- (trifluoromethyl) benzene To give 140 mg (77% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.12 min; m / z = 528 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.55-1.60 (m, 2H), 1.64-1.69 (m, 2H) ), 2.46 (s, partially hidden by the DMSO signal), 3.26 (s, 3H), 4.19 (q, 2H), 5.07 (s, 2H), 7.17. -7.25 (m, 2H), 7.32-7.37 (m, 2H), 7.44 (dd, 1H), 7.57-7.63 (m, 1H), 8.42 (s) 1H).

Example 67
1- (1'-methyl-2'-oxo-1 ', 2'-dihydrospiro [cyclopropane-1,3'-indole] -5'-yl) -2,4-dioxo-3-[(1R ) -4- (Trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer)

  First, 1- (1′-methyl-2′-oxo-1 ′, 2′-dihydrospiro [cyclopropane-1,3′-indole] -5′-yl) -2,4 from Example 63A. -8.00 g (22.5 mmol) of ethyl dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, (1S) -4- (trifluoromethyl) indan-1-ol (from Example 14A 5.46 g (27.0 mmol) and 10.0 g (38.26 mmol) of triphenylphosphine were placed in THF / DMF 1: 1 (215 mL) under argon at room temperature. To this mixture, 7.09 mL (36.02 mmol) of diisopropyl azodicarboxylate was added dropwise with stirring. After 1 hour, an additional 1.2 g (4.51 mmol) of triphenylphosphine and 0.89 mL (4.51 mmol) of diisopropyl azodicarboxylate were added. The reaction mixture was stirred at room temperature for an additional 1.5 hours. While cooling with ice, the mixture was mixed with 10 mL of 1M hydrochloric acid, stirred for 15 minutes and then extracted with ethyl acetate. The combined organic phases were washed twice with 1M hydrochloric acid, then twice with saturated sodium carbonate solution and once with saturated sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was stirred with 100 mL MTBE and left overnight. The formed solid was filtered and discarded. The filtrate was concentrated on a rotary evaporator. The residue was taken up in a little dichloromethane and purified by flash chromatography (eluent: cyclohexane / ethyl acetate 1: 2). This gave 7.81 g (59% of theory, purity 92% by NMR) of the title compound.

LC-MS (Method 4): Rt = 2.49 min; m / z = 540 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.31 (t, 3H), 1.54-1.61 (m, 2H), 1.69-1.81 (m, 2H) ), 2.35-2.49 (m, 1H), 2.51-2.66 (m, 1H), 3.05-3.21 (m, 1H), 3.28 (s, 3H), 3.39-3.54 (m, 1H), 4.28 (q, 2H), 6.54-6.67 (m, 1H), 6.80 (br.s, 1H), 6.97 ( d, 1H), 7.19 (d, 1H), 7.24-7.36 (m, 2H), 7.49 (d, 1H), 8.26 (s, 1H).

Specific rotation: α _D ²⁰ = + 131.7 °, (chloroform, c = 0.405 g / 100 mL).

Example 68
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -2,4-dioxo -1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  1- (3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 65A To a solution of 629 mg (1.83 mmol) of ethyl 5-carboxylate in DMF (10 mL), 551 mg (2.02 mmol) of 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene, 506 mg of potassium carbonate (3 .66 mmol) and 30 mg (0.18 mmol) of potassium iodide were added and the mixture was stirred at 60 ° C. for 1.5 hours. For workup, the reaction mixture was mixed with water and the precipitate formed was filtered off with suction and washed with water. The crude product so obtained was purified by flash silica gel chromatography (dichloromethane / methanol, 98: 2). This gave 371 mg (purity 88%, 33% of theory) of the target compound.

LC-MS (Method 1): Rt = 1.11 min; MS (ESI cation): m / z = 536 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (s, 3H), 1.28 (s, 6H), 4.19 (q, 2H), 5.13 (s, 2H), 7.04-7.07 (m, 1H), 7.11-7.15 (m, 1H), 7.44-7.47 (m, 1H), 7.48-7.54 ( m, 1H), 7.59-7.63 (m, 1H), 7.77-7.82 (m, 1H), 8.47 (s, 1H), 10.61 (s, 1H).

Example 69
1- (1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl) -3- [2-chloro-3- (trifluoromethyl) benzyl] -2,4-dioxo -1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 1. The reaction time was 2 hours. 1- (1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 66A Starting from 200 mg (0.53 mmol) of ethyl 5-carboxylate and 162 mg (0.59 mmol) of 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene, 228 mg (71% of theory) of the title compound )

LC-MS (Method 1): Rt = 1.18 min; m / z = 564 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.34 (s, 6H), 2.18 (s, 3H), 3.94 (s, 2H), 4.19 (q, 2H), 5.12 (s, 2H), 7.19 (dd, 1H), 7.40 (d, 1H), 7.50 (t, 1H), 7. 60 (d, 1H), 7.79 (d, 1H), 8.14 (s, 1H), 8.41 (s, 1H).

Example 70
1- (1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo -1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 1. The reaction time was 2 hours. 1- (1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 66A Starting from 200 mg (0.53 mmol) of ethyl 5-carboxylate and 149 mg (0.59 mmol) of 1- (bromomethyl) -2-methyl-3- (trifluoromethyl) benzene, 253 mg (84% of theory) of the title compound )

LC-MS (Method 1): Rt = 1.22 min; m / z = 544 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.34 (s, 6H), 2.18 (s, 3H), 2.45 (s, 3H), 3.93 (s, 2H), 4.19 (q, 2H), 5.06 (s, 2H), 7.19 (dd, 1H), 7.33 (t, 1H), 7. 40 (d, 2H), 7.59 (d, 1H), 8.13 (d, 1H), 8.39 (s, 1H).

Example 71
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-1H-benzotriazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5 ethyl carboxylate

  First, 162 mg of ethyl 1- (1-methyl-1H-benzotriazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 74A (0 .51 mmol) was taken up in 6.5 mL of DMF. 155 mg (0.56 mmol) of 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene, 142 mg (1.03 mmol) of potassium carbonate and 9 mg (52 μmol) of potassium iodide are added, and the reaction mixture is heated at 60 ° C. Stir for 5 hours. After cooling to room temperature, water was added to the mixture. The precipitate was filtered, washed with a small amount of water and MTBE and dried at 50 ° C. in a drying cabinet. This gave 149 mg (purity 95%, 54% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.03 min; m / z = 508 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 4.21 (q, 2H), 4.37 (s, 3H), 5.17 (s, 2H), 7.51-7.57 (m, 1H), 7.61-7.65 (m, 1H), 7.71-7.75 (m, 1H), 7.79-7.83 ( m, 1H), 7.99-8.02 (m, 1H), 8.31-8.33 (m, 1H), 8.61 (s, 1H).

Example 72
1- (1-Methyl-1H-benzotriazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5 ethyl carboxylate

  The title compound was prepared and purified as in Example 71. 162 mg (0.51 mmol) of ethyl 1- (1-methyl-1H-benzotriazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 74A Starting from 143 mg (0.56 mmol) of 1- (bromomethyl) -2-methyl-3- (trifluoromethyl) benzene, 152 mg (59% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.02 min; m / z = 488 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 2.47 (s, partially hidden by DMSO signal), 4.20 (q, 2H), 4.37 (s, 3H), 5.10 (s, 2H), 7.33-7.39 (m, 1H), 7.40-7.45 (m, 1H), 7.58. -7.64 (m, 1H), 7.73 (dd, 1H), 8.00 (d, 1H), 8.32-8.34 (m, 1H), 8.58 (s, 1H).

Example 73
Ethyl 3- (2,3-dichlorobenzyl) -1- (1-methyl-1H-benzotriazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 71. 162 mg (0.51 mmol) of ethyl 1- (1-methyl-1H-benzotriazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 74A Starting from 136 mg (0.56 mmol) and 2,3-dichlorobenzyl bromide, 188 mg (74% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.99 min; m / z = 474 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 4.20 (q, 2H), 4.37 (s, 3H), 5.12 (s, 2H), 7.27 (d, 1H), 7.35 (t, 1H), 7.59 (d, 1H), 7.72 (d, 1H), 8.00 (d, 1H), 8. 32 (s, 1H), 8.59 (s, 1H).

Example 74
3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- (1-methyl-1H-benzotriazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5 ethyl carboxylate

  First, 162 mg of ethyl 1- (1-methyl-1H-benzotriazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 74A (0 .51 mmol) in DMF (6 mL), 238 mg of 1- (bromomethyl) -3-chloro-2- (trifluoromethyl) benzene (purity 65%, 0.56 mmol), 142 mg of potassium carbonate (1.03 mmol) and Potassium iodide 8 mg (0.05 mmol) was added. The reaction mixture was then stirred at 60 ° C. for 5 hours. The mixture cooled to room temperature was mixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was stirred with cyclohexane / ethyl acetate and the precipitated solid was filtered off with suction and dried in vacuo. This gave 115 mg (43% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.02 min; m / z = 508 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 4.21 (q, 2H), 4.37 (s, 3H), 5.23 (br. s, 2H), 7.36-7.41 (m, 1H), 7.58-7.67 (m, 2H), 7.70-7.75 (m, 1H), 8.00 (d, 1H), 8.30-8.33 (m, 1H), 8.62 (s, 1H).

Example 75
1- (1-Methyl-1H-indazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 5-ethyl carboxylate

  The title compound was prepared and purified as in Example 1. The reaction time was 2 hours. 200 mg (0.63 mmol) of ethyl 1- (1-methyl-1H-indazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 75A Starting from 177 mg (0.70 mmol) of 1- (bromomethyl) -2-methyl-3- (trifluoromethyl) benzene, 254 mg (80% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.11 min; m / z = 487 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 2.46 (s, 3H), 4.10 (s, 3H), 4.19 (q, 2H), 5.09 (s, 2H), 7.32-7.44 (m, 2H), 7.54 (d, 1H), 7.60 (d, 1H), 7.78 (d, 1H) ), 7.98 (s, 1H), 8.18 (s, 1H), 8.49 (s, 1H).

Example 76
1- (1-Methyl-1H-indazol-5-yl) -2,4-dioxo-3-[(1R) -4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl ] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer)

  First, 200 mg of ethyl 1- (1-methyl-1H-indazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 75A. 63 mmol) and 500 mg (1.90 mmol) of triphenylphosphine were placed in THF / DMF 1: 1 (8.4 mL) under argon and cooled to −30 ° C. A solution of 257 mg (1.27 mmol) of diisopropyl azodicarboxylate and 154 mg (0.76 mmol) of (1S) -4- (trifluoromethyl) indan-1-ol from Example 14A in THF (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. For workup, the reaction mixture was cooled to −40 ° C., mixed with 1M hydrochloric acid, warmed to room temperature and extracted with ethyl acetate. The organic phase was washed successively with 1M hydrochloric acid twice and saturated sodium chloride solution once, dried over magnesium sulfate and concentrated. The residue was purified by HPLC (Method 8). This gave 142 mg (43% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.11 min; m / z = 499 (M + H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 1.36 (t, 3H), 2.40-2.52 (m, 1H), 2.53-2.61 (m, 1H, part Concealed by the DMSO signal), 3.08-3.19 (m, 1H), 3.45-3.58 (m, 1H), 4.11 (s, 3H), 4.35 ( q, 2H), 6.61-6.77 (m , 1H), 7.23-7.33 (m, 3H, hidden by partially CDCl ₃ signal), 7.44-7.53 (M, 2H), 7.69 (s, 1H), 8.04 (s, 1H), 8.37 (s, 1H).

Specific rotation: α _D ²⁰ = + 146.6 °, (chloroform, c = 0.405 g / 100 mL).

Example 77
1- (1-Methyl-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5 ethyl carboxylate

  First, 1.00 g of ethyl 1- (1-methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 76A. (3.18 mmol) in DMF (8 mL), 886 mg (3.50 mmol) of 1- (bromomethyl) -2-methyl-3- (trifluoromethyl) benzene, 879 mg (6.36 mmol) of potassium carbonate and 5 iodine 3 mg (0.32 mmol) of potassium halide was added. The reaction mixture was then stirred at 60 ° C. for 5 hours. The mixture was cooled to room temperature and mixed with water, the precipitate was filtered off with suction, washed with water and ethanol / MTBE and dried at 50 ° C. in vacuo. This gave 1.06 g (68% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.93 min; m / z = 487 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 2.46 (s, 3H), 3.89 (s, 3H), 4.19 (q, 2H), 5.09 (s, 2H), 7.32-7.46 (m, 3H), 7.60 (d, 1H), 7.71 (d, 1H), 7.89 (d, 1H) ), 8.33 (s, 1H), 8.46 (s, 1H).

Example 78
3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- (1-methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5 ethyl carboxylate

  The title compound was prepared and purified as in Example 77. 200 mg (0.63 mmol) of ethyl 1- (1-methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 76A Starting from 295 mg (purity 65%, 0.70 mmol) and 1- (bromomethyl) -3-chloro-2- (trifluoromethyl) benzene, 82 mg (26% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.97 min; m / z = 507 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.89 (s, 3H), 4.20 (q, 2H), 5.23 (s, 2H), 7.36 (d, 1H), 7.41-7.46 (m, 1H), 7.57-7.67 (m, 2H), 7.70 (d, 1H), 7.87. (D, 1H), 8.32 (s, 1H), 8.49 (s, 1H).

Example 79
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5 ethyl carboxylate

  The title compound was produced in the same manner as in Example 77. 200 mg (0.63 mmol) of ethyl 1- (1-methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 76A And further purification by preparative HPLC (Method 8) starting from 191 mg (0.70 mmol) of 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene and 153 g (theoretical amount of the title compound). 47%).

LC-MS (Method 1): Rt = 0.97 min; m / z = 507 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.89 (s, 3H), 4.20 (q, 2H), 5.16 (s, 2H), 7.44 (dd, 1H), 7.50-7.56 (m, 1H), 7.59-7.63 (m, 1H), 7.71 (d, 1H), 7.78. -7.83 (m, 1H), 7.88 (d, 1H), 8.33 (s, 1H), 8.49 (s, 1H).

Example 80
1- (1-Ethyl-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5 ethyl carboxylate

  First, 122.5 mg of ethyl 1- (1-ethyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 46A (0.37 mmol) and 103 mg (0.41 mmol) of 1- (bromomethyl) -2-methyl-3- (trifluoromethyl) benzene were placed in DMF (4 mL) and 103 mg (0.74 mmol) of potassium carbonate and iodinated. Potassium 6 mg (0.04 mmol) was added. The reaction mixture was stirred at 60 ° C. for 5 hours, then brought to room temperature and mixed with water. The precipitate was filtered off with suction, washed with water and MTBE and dried in vacuo at 50 ° C. overnight. This gave 38 mg (19% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.97 min; m / z = 501 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.43 (t, 3H), 2.46 (s, 3H), 4.19 (q, 2H), 4.33 (q, 2H), 5.09 (s, 2H), 7.31-7.46 (m, 3H), 7.60 (d, 1H), 7.76 (d, 1H) ), 7.89 (d, 1H), 8.40 (s, 1H), 8.48 (s, 1H), 8.48 (s, 1H).

Example 81
1- (2-carbamoyl-1-methyl-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3 4-tetrahydropyrimidine-5-carboxylate ethyl

  First, 1- (2-carbamoyl-1-methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid from Example 81A 158 mg (0.44 mmol) of ethyl is placed in DMF (3 mL) and 123 mg (0.48 mmol) of 1- (bromomethyl) -2-methyl-3- (trifluoromethyl) benzene, 122 mg (0.88 mmol) of potassium carbonate and 7 mg (0.04 mmol) of potassium iodide was added. The reaction mixture was stirred at 80 ° C. for 1 hour. The cooled mixture was mixed with water and the precipitated solid was filtered and washed with water. The filtrate was extracted twice with dichloromethane and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was combined with the previously isolated solid and purified by preparative HPLC (Method 8). This gave 131 mg (54% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.98 min; m / z = 530 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 2.47 (s, partially hidden by the DMSO signal), 4.16 (s, 3H), 4.20 (q, 2H), 5.10 (s, 2H), 7.33-7.39 (m, 1H), 7.39-7.44 (m, 1H), 7.53 -7.63 (m, 2H), 7.82 (d, 1H), 7.92 (br.s, 1H), 7.96-8.00 (m, 1H), 8.32 (br.s) 1H), 8.50 (s, 1H).

Example 82
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-1H-benzimidazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5 ethyl carboxylate

  The title compound was prepared and purified as in Example 80. The reaction time was 1 hour. 150 mg (0.47 mmol) of ethyl 1- (1-methyl-1H-benzimidazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 82A And 110 mg of the title compound after further purification by flash chromatography (dichloromethane / methanol 98: 2) starting from 143 mg (0.52 mmol) of 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene. (44% of theory) was obtained.

LC-MS (Method 1): Rt = 0.92 min; m / z = 507 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.87 (s, 3H), 4.20 (q, 2H), 5.17 (s, 2H), 7.37 (dd, 1H), 7.54 (t, 1H), 7.61 (d, 1H), 7.77 (d, 1H), 7.81 (d, 1H), 7. 84 (d, 1H), 8.34 (s, 1H), 8.52 (s, 1H).

Example 83
1- (1-Ethyl-2-methyl-1H-benzimidazol-5-yl) -3- [3-fluoro-2- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3 4-tetrahydropyrimidine-5-carboxylate ethyl

  First, 1- (1-ethyl-2-methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid from Example 117A 200 mg (0.58 mmol) of ethyl was placed in DMF (7 mL) and 165 mg (0.64 mmol) of 1- (bromomethyl) -3-fluoro-2- (trifluoromethyl) benzene, 161 mg (1.17 mmol) of potassium carbonate and Mixed with 10 mg (0.06 mmol) of potassium iodide. The reaction mixture was stirred at 60 ° C. for 5 hours. The cooled mixture was mixed with water and the precipitated solid was filtered and washed with water. The solid was dissolved in dichloromethane and purified by flash silica gel chromatography (dichloromethane / methanol, 30: 1). This gave 153 mg (50% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.85 min; m / z = 519 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 1.32 (t, 3H), 2.58 (s, 3H), 4.19 (q, 2H), 4.28 (q, 2H), 5.21 (s, 2H), 7.22 (d, 1H), 7.33 (d, 1H), 7.41 (t, 1H), 7. 61-7.70 (m, 2H), 7.70-7.75 (m, 1H), 8.44-8.50 (m, 1H).

Example 84
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-ethyl-2-methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3 4-tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 83. 200 mg of ethyl 1- (1-ethyl-2-methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 117A Starting from 175 mg (0.63 mmol) of 0.58 mmol) and 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene, 114 mg (36% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.89 min; m / z = 535 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.31 (t, 3H), 2.58 (s, 3H), 4.19 (q, 2H), 4.27 (q, 2H), 5.16 (s, 2H), 7.35 (dd, 1H), 7.53 (t, 1H), 7.60 (d, 1H), 7. 65 (d, 1H), 7.73 (d, 1H), 7.80 (d, 1H), 8.47 (s, 1H).

Example 85
1- (1-cyclohexyl-2-methyl-1H-benzimidazol-5-yl) -3- [3-fluoro-2- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3 4-tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 83. 200 mg of ethyl 1- (1-cyclohexyl-2-methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 118A ( Starting from 142 mg (0.55 mmol) of 0.50 mmol) and 1- (bromomethyl) -3-fluoro-2- (trifluoromethyl) benzene, 90 mg (30% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.05 min; m / z = 573 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.34 to 1.57 (m, 3H), 1.67-1.75 (m, 1H) ), 1.82-1.92 (m, 4H), 2.10-2.23 (m, 2H), 2.60 (s, 3H), 4.19 (q, 2H), 4.26- 4.37 (m, 1H), 5.20 (s, 2H), 7.22 (d, 1H), 7.29 (dd, 1H), 7.36-7.45 (m, 1H), 7 .62-7.70 (m, 1H), 7.71 (d, 1H), 7.83 (d, 1H), 8.47 (s, 1H).

Example 86
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-isopropyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5 ethyl carboxylate

  The title compound was produced in the same manner as in Example 83. 200 mg (0.58 mmol) of ethyl 1- (1-isopropyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 51A And after purification by flash chromatography (dichloromethane / methanol 50: 1) starting from 175 mg (0.64 mmol) of 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene 64 mg (theoretical) 19% of the amount) was obtained.

LC-MS (Method 1): Rt = 1.05 min; m / z = 535 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.56 (d, 6H), 4.19 (q, 2H), 4.82 (spt, 1H), 5.16 (s, 2H), 7.42 (dd, 1H), 7.54 (t, 1H), 7.61 (d, 1H), 7.80 (d, 2H), 7. 88 (d, 1H), 8.49 (s, 1H), 8.51 (s, 1H).

Example 87
Ethyl 3- (2,3-dichlorobenzyl) -1- (1-isopropyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was produced in the same manner as in Example 83. 200 mg (0.58 mmol) of ethyl 1- (1-isopropyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 51A After purification by flash chromatography (dichloromethane / methanol 50: 1) starting from 154 mg (0.64 mmol) and 1- (bromomethyl) -2,3-dichlorobenzene, 83 mg (28% of theory) of the title compound are obtained. Obtained.

LC-MS (Method 1): Rt = 1.02 min; m / z = 501 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.56 (d, 6H), 4.19 (q, 2H), 4.82 (spt, 1H), 5.11 (s, 2H), 7.26 (d, 1H), 7.34 (t, 1H), 7.42 (dd, 1H), 7.58 (d, 1H), 7. 79 (d, 1H), 7.88 (d, 1H), 8.49 (s, 2H).

Example 88
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-cyclobutyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5 ethyl carboxylate

  200 mg (0.56 mmol) ethyl 1- (1-cyclobutyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 41A The title compound was prepared in the same manner as in Example 83 using 169 mg (0.62 mmol) of 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene. For workup, the reaction mixture was mixed with water and the precipitate was filtered off with suction, washed with water and MTBE and dried in vacuo at 50 ° C. overnight. The solid was purified by flash chromatography (dichloromethane / methanol 70: 1). The fraction containing the product was concentrated, and the residue was extracted and stirred with ethanol, filtered, washed with ethanol, and dried under high vacuum. This gave 141 mg (42% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.06 min; m / z = 547 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.86-1.96 (m, 2H), 2.56 (s, 4H, partially (Hidden by DMSO signal) 4.20 (q, 2H), 5.04 (quintray, 1H), 5.16 (s, 2H), 7.42 (dd, 1H), 7.53 (T, 1H), 7.62 (d, 1H), 7.74 (d, 1H), 7.81 (d, 1H), 7.89 (d, 1H), 8.50 (s, 1H) 8.55 (s, 1H).

Example 89
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-1H-indazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 5-ethyl carboxylate

  The title compound was prepared and purified as in Example 80. 200 mg (0.63 mmol) of ethyl 1- (1-methyl-1H-indazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 75A Starting from 191 mg (0.70 mmol) of 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene, 228 mg (67% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.11 min; m / z = 507 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (t, 3H), 4.10 (s, 3H), 4.20 (q, 2H), 5.16 (s, 2H), 7.49-7.57 (m, 2H), 7.62 (d, 1H), 7.74-7.84 (m, 2H), 7.98 (d, 1H), 8.18. (S, 1H), 8.52 (s, 1H).

Example 90
1- (1-Ethyl-1H-benzimidazol-5-yl) -3- [3-fluoro-2- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5 ethyl carboxylate

  The title compound was prepared and purified as in Example 1. 122.5 mg of ethyl 1- (1-ethyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 46A. 37 mg) and 1- (bromomethyl) -3-fluoro-2- (trifluoromethyl) benzene 105 mg (0.41 mmol) gave 73 mg (35% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.92 min; m / z = 505 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.43 (t, 3H), 4.20 (q, 2H), 4.33 (q, 2H), 5.21 (br.s, 2H), 7.22 (d, 1H), 7.36-7.46 (m, 2H), 7.67 (q, 1H), 7.76 (d 1H), 7.84-7.90 (m, 1H), 8.40 (s, 1H), 8.51 (s, 1H).

Example 91
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-ethyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5 ethyl carboxylate

  The title compound was produced in the same manner as in Example 80. 122.5 mg of ethyl 1- (1-ethyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 46A. 37 mmol) and 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene 112 mg (0.41 mmol) and after further purification by flash chromatography (dichloromethane / methanol 30: 1), the title 52 mg (27% of theory) of compound were obtained.

LC-MS (Method 1): Rt = 1.01 min; m / z = 521 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 1.43 (t, 3H), 4.20 (q, 2H), 4.34 (q, 2H), 5.16 (s, 2H), 7.43 (dd, 1H), 7.53 (t, 1H), 7.61 (d, 1H), 7.76 (d, 1H), 7. 81 (d, 1H), 7.88 (d, 1H), 8.40 (s, 1H), 8.50 (s, 1H).

Example 92
3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- [1- (cyclopropylmethyl) -1H-benzimidazol-5-yl] -2,4-dioxo-1,2,3 4-tetrahydropyrimidine-5-carboxylate ethyl

  First, 1- [1- (cyclopropylmethyl) -1H-benzimidazol-5-yl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid from Example 56A 200 mg (0.56 mmol) of ethyl was placed in 7.1 mL of DMF. 156 mg (1.13 mmol) of potassium carbonate, 9 mg (0.05 mmol) of potassium iodide and 261 mg of 1- (bromomethyl) -3-chloro-2- (trifluoromethyl) benzene (purity 65%, 0.62 mmol) were added, The mixture was heated to 60 ° C. for 5 hours. The cooled reaction mixture was mixed with water and extracted twice with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue was stirred in ethanol and the precipitated solid was filtered off with suction and dried with a high vacuum pump. This gave 137 mg (44% of theory) of the title compound. The filtrate was concentrated and the residue was purified by flash chromatography (dichloromethane / methanol 50: 1). An additional 56 mg (total yield: 61% of theory) of the title compound could then be isolated.

LC-MS (Method 3): Rt = 1.29 min; m / z = 547 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.40-0.48 (m, 2H), 0.51-0.58 (m, 2H), 1.23 (t, 3H ), 1.27-1.37 (m, 1H), 4.14-4.24 (m, 4H), 5.23 (s, 2H), 7.36 (d, 1H), 7.42 ( dd, 1H), 7.56-7.68 (m, 2H), 7.81 (d, 1H), 7.87 (d, 1H), 8.43 (s, 1H), 8.53 (s) 1H).

Example 93
1- (1-Isopropyl-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5 ethyl carboxylate

  The title compound was produced in the same manner as in Example 80. 200 mg (0.58 mmol) of ethyl 1- (1-isopropyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 51A After further purification by flash chromatography (dichloromethane / methanol 50: 1) starting from 162 mg (0.64 mmol) of 1- (bromomethyl) -2-methyl-3- (trifluoromethyl) benzene and 90 mg of the title compound (29% of theory) was obtained.

LC-MS (Method 1): Rt = 1.04 min; m / z = 515 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 1.56 (d, 6H), 2.46 (s, 3H), 4.19 (q, 2H), 4.82 (spt, 1H), 5.09 (s, 2H), 7.32-7.46 (m, 3H), 7.60 (d, 1H), 7.80 (d, 1H) ), 7.89 (d, 1H), 8.48 (d, 2H).

Example 94
1- (1,3-Dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl ] -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 1. The reaction time was 2 hours. 1- (1,3-Dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl) -2,4-dioxo-1,2, from Example 87A Starting from 160 mg (0.42 mmol) of ethyl 3,4-tetrahydropyrimidine-5-carboxylate and 117 mg (0.46 mmol) of 1- (bromomethyl) -2-methyl-3- (trifluoromethyl) benzene 195 mg (84% of theory) were obtained.

LC-MS (Method 1): Rt = 1.10 min; m / z = 553 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 2.46 (s, 3H), 3.26 (s, 3H), 3.30 (s, 3H), 4.20 (q, 2H), 5.08 (s, 2H), 7.15 (d, 1H), 7.23 (dd, 1H), 7.29 (d, 1H), 7. 31-7.39 (m, 2H), 7.58-7.63 (m, 1H), 8.45 (s, 1H).

Example 95
3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- (1,3-dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl ) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 1. The reaction time was 2 hours. 1- (1,3-Dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl) -2,4-dioxo-1,2, from Example 87A 160 mg (0.42 mmol) of ethyl 3,4-tetrahydropyrimidine-5-carboxylate and 1- (bromomethyl) -3-chloro-2- (trifluoromethyl) benzene (preparation: WO 2004/52858, p. 149, Example 176) Reference) Starting from 194 mg (65% purity, 0.46 mmol), after further purification by flash chromatography (dichloromethane / methanol 250: 1), 120 mg (50% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.11 min; m / z = 573 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.27 (s, 3H), 3.30 (s, 3H), 4.20 (q, 2H), 5.21 (br.s, 2H), 7.17 (d, 1H), 7.21 (dd, 1H), 7.26 (d, 1H), 7.32 (d, 1H), 7.56-7.67 (m, 2H), 8.49 (s, 1H).

Example 96
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1,3-dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl ) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 1. 1- (1,3-Dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl) -2,4-dioxo-1,2, from Example 87A Starting from 160 mg (0.42 mmol) of ethyl 3,4-tetrahydropyrimidine-5-carboxylate and 126 mg (0.46 mmol) of 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene, the title compound 167 mg (69% of theory) were obtained.

LC-MS (Method 1): Rt = 1.11 min; m / z = 573 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 3.27 (s, 3H), 3.31 (s, 3H), 4.20 (q, 2H), 5.15 (s, 2H), 7.16 (d, 1H), 7.22 (dd, 1H), 7.27 (d, 1H), 7.49-7.60 (m, 2H) ), 7.80 (d, 1H), 8.48 (s, 1H).

Example 97
1- (1,3-Dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl) -2,4-dioxo-3-[(1R) -4- (Trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer)

  The title compound was prepared and purified as in Example 42 (Method A). 1- (1,3-Dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl) -2,4-dioxo-1,2, from Example 87A Starting from 200 mg (0.52 mmol) of ethyl 3,4-tetrahydropyrimidine-5-carboxylate and 127 mg (0.63 mmol) of (1S) -4- (trifluoromethyl) indan-1-ol from Example 14A 149 mg (50% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.15 min; m / z = 565 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 2.35-2.43 (m, 1H), 2.43-2.48 (m, 1H) , Partially hidden by DMSO signal), 3.03-3.15 (m, 1H), 3.22-3.27 (m, 4H), 3.29 (s, 3H), 4. 17 (q, 2H), 6.31-6.59 (m, 1H), 7.09-7.31 (m, 3H), 7.36 (t, 1H), 7.47 (d, 1H) 7.53 (d, 1H), 8.37 (s, 1H).

Example 98
1- (1,3-Benzothiazol-6-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5 -Ethyl carboxylate

  The title compound was prepared and purified as in Example 80. 200 mg (0.63 mmol) of ethyl 1- (1,3-benzothiazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 88A and 1 Starting from 175 mg (0.69 mmol) of-(bromomethyl) -2-methyl-3- (trifluoromethyl) benzene, 204 mg (65% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.08 min; m / z = 490 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 2.46 (s, 3H), 4.20 (q, 2H), 5.10 (s, 2H), 7.36 (t, 1H), 7.42 (d, 1H), 7.60 (d, 1H), 7.73 (dd, 1H), 8.22 (d, 1H), 8. 41 (d, 1H), 8.59 (s, 1H), 9.54 (s, 1H).

Example 99
1- (4-Methylquinolin-7-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carvone Ethyl acid

  The title compound was prepared and purified as in Example 80. 200 mg (0.61 mmol) of ethyl 1- (4-methylquinolin-7-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example 93A and 1- ( Starting from 171 mg (0.67 mmol) of bromomethyl) -2-methyl-3- (trifluoromethyl) benzene, 230 mg (75% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.13 min; m / z = 498 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (t, 3H), 2.47 (s, 3H), 2.74 (s, 3H), 4.21 (q, 2H), 5.11 (s, 2H), 7.33-7.39 (m, 1H), 7.43-7.47 (m, 1H), 7.48-7.51 (m, 1H) 7.59-7.63 (m, 1H), 7.77-7.81 (m, 1H), 8.22-8.27 (m, 2H), 8.62 (s, 1H), 8 .85 (d, 1H).

Example 100
1- (1-methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2, 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 1. The reaction time was about 16 hours. 1- (1-Methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl) -2,4-dioxo-1,2,3,4 from Example 92A Starting from 200 mg (0.57 mmol) of ethyl tetrahydropyrimidine-5-carboxylate and 161 mg (0.63 mmol) of 1- (bromomethyl) -2-methyl-3- (trifluoromethyl) benzene, 255 mg (theoretical) Of 85%).

LC-MS (Method 1): Rt = 1.07 min; m / z = 518 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 2.46 (s, 3H), 3.30 (s, partly hidden by water signal 4.20 (q, 2H), 5.07 (s, 2H), 5.30 (s, 2H), 7.24 (d, 1H), 7.30-7.41 (m, 2H) ), 7.47 (d, 1H), 7.54-7.62 (m, 2H), 8.44 (s, 1H).

Example 101
1- (1-Methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl) -2,4-dioxo-3-[(1R) -4- (trifluoromethyl ) -2,3-Dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate

  The title compound was prepared and purified as in Example 67. 1- (1-Methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl) -2,4-dioxo-1,2,3,4 from Example 92A Starting from 200 mg (0.56 mmol) of ethyl tetrahydropyrimidine-5-carboxylate and 140 mg (0.69 mmol) of (1S) -4- (trifluoromethyl) indan-1-ol from Example 14A, HPLC (method After purification according to 8), 160 mg (51% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.07 min; m / z = 530 (M + H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 1.36 (t, 3H), 2.37-2.48 (m, 1H), 2.53-2.60 (m, 1H), 3.08-3.19 (m, 1H), 3.39 (s, 3H), 3.45-3.58 (m, 1H), 4.36 (q, 2H), 5.21 (s, 2H), 6.61-6.73 (m, 1H ), 7.03 (d, 1H), 7.13 (s, 1H), 7.26 ( hidden d, 3H, a portion Tekki by CHCl ₃ signal 7.47 (d, 1H), 8.26-8.30 (m, 1H).

Specific rotation: α _D ²⁰ = + 124.4 ° (chloroform, c = 0.360 g / 100 mL).

Example 102
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 80. 1- (1-Methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5 from Example 91A Starting from 200 mg (0.58 mmol) of ethyl carboxylate and 162 mg (0.64 mmol) of 1- (bromomethyl) -2-methyl-3- (trifluoromethyl) benzene, 267 mg (89% of theory) of the title compound Got.

LC-MS (Method 1): Rt = 1.06 min; m / z = 516 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 2.46 (s, 3H), 2.58 (t, 2H), 2.92 (t, 2H), 3.28 (s, 3H), 4.19 (q, 2H), 5.08 (s, 2H), 7.22 (d, 1H), 7.31-7.39 (m, 2H) ), 7.40-7.46 (m, 2H), 7.60 (d, 1H), 8.41 (s, 1H).

Example 103
1- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2,4-dioxo-3-[(1R) -4- (trifluoromethyl) -2, 3-Dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer)

  First, 1- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2,4-dioxo-1,2,3,4-tetrahydro from Example 91A. 200 mg (0.58 mmol) of ethyl pyrimidine-5-carboxylate and 475 mg (1.81 mmol) of triphenylphosphine were placed in THF / DMF 1: 1 (7.6 mL) under argon. 235 mg (1.16 mmol) of diisopropyl azodicarboxylate was added dropwise, followed by 141 mg (0.69 mmol) of (1S) -4- (trifluoromethyl) indan-1-ol from Example 14A. The reaction mixture was stirred at room temperature for 16 hours. For workup, the mixture was mixed with 1M hydrochloric acid, diluted with ethyl acetate and the phases were separated. The organic phase was washed sequentially with 1M hydrochloric acid twice and saturated sodium chloride solution once, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 8). This gave 125 mg (40% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.09 min; m / z = 528 (M + H) ^<+> .

¹ H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 1.36 (t, 3H), 2.38-2.50 (m, 1H), 2.53-2.61 (m, 1H, part 2.67 (t, 2H), 2.94 (t, 2H), 3.08-3.19 (m, 1H), 3.36 (s, 3H) 3.46-3.58 (m, 1H), 4.36 (q, 2H), 6.62-6.74 (m, 1H), 7.05 (d, 1H), 7.13 (s) 1H), 7.18-7.23 (m, 1H), 7.24-7.30 (m, 2H), 7.47 (d, 1H), 8.29 (s, 1H).

Specific rotation: α _D ²⁰ = + 128.5 °, (chloroform, c = 0.415 g / 100 mL).

Example 104
1- (6-Fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3-[(1R) -4- (tri Fluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer)

  First, 1- (6-fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2 from Example 95A. , 3,4-tetrahydropyrimidine-5-carboxylate 200 mg (0.55 mmol) and triphenylphosphine 434 mg (1.66 mmol) were placed in THF / DMF 1: 1 (7.3 mL) under argon and cooled. It was −30 ° C. 218 μL (1.10 mmol) diisopropyl azodicarboxylate, then a solution of 134 mg (0.66 mmol) of (1S) -4- (trifluoromethyl) indan-1-ol from Example 14A in THF (3 mL) was added dropwise. . The reaction mixture was warmed to room temperature and stirred at room temperature for 30 minutes. For workup, the reaction mixture was cooled to 0 ° C., mixed with 5 mL of 1M hydrochloric acid, and then extracted with ethyl acetate at room temperature. The organic phase was washed successively with 1M hydrochloric acid twice and saturated sodium chloride solution once, dried over magnesium sulfate and concentrated. The residue was extracted and stirred with ethanol and the precipitated solid was filtered off with suction and discarded. The filtrate was concentrated on a rotary evaporator, dissolved in a small amount of dichloromethane and purified by flash chromatography (eluent: dichloromethane / methanol 120: 1 to 20: 1). The resulting product was dried under HV and then stirred in 10 mL of cyclohexane / ethyl acetate 1: 1. The solid was filtered and dried under HV. This gave 146 mg (47% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.10 min; m / z = 547 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 2.30-2.42 (m, 1H), 2.52 to 2.53 (m, 1H) , Partially hidden by the DMSO signal), 3.04-3.15 (m, 1H), 3.22-3.30 (m, 1H), 3.32 (s, 3H), 3. 35 (s, 3H), 4.19 (q, 2H), 6.37-6.57 (m, 1H), 7.33-7.50 (m, 4H), 7.54 (d, 1H) 8.48 (s, 1H).

Example 105
3-[(3-Chloro-4-methyl-2-thienyl) methyl] -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2, 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  To a solution of 33 mg (0.20 mmol) and 74 mg (0.28 mmol) of (3-chloro-4-methyl-2-thienyl) methanol from Example 96A, initially placed under argon, in dry THF (2 mL) at room temperature. Was added dropwise 45 μL (0.23 mmol) of diisopropyl azodicarboxylate. After 5 minutes, 1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3 from Example 2A. 65 mg (0.18 mmol) of ethyl 4-tetrahydropyrimidine-5-carboxylate was added and the reaction mixture was stirred at room temperature overnight. For workup, 3 drops of 1N hydrochloric acid were added and the entire reaction mixture was separated by preparative HPLC (Method 8). The product containing fractions were concentrated on a rotary evaporator and the residue was stirred in diethyl ether. The solid was filtered off with suction and dried under high vacuum. This gave 26 mg (26% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.00 min; m / z = 489 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 2.12 (s, 3H), 3.30 (s, 3H, partly due to water signal 3.37 (s, 3H), 4.19 (q, 2H), 5.19 (s, 2H), 7.14-7.23 (m, 1H), 7.24-7 .32 (m, 2H), 7.38 (s, 1H), 8.36 (s, 1H).

Example 106
3- (4,6-Difluoro-2,3-dihydro-1H-inden-1-yl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5 Yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

  1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo from Example 2A initially placed at −40 ° C. under argon. Diisopropyl azodicarboxylate in a solution of ethyl 1,2,3,4-tetrahydropyrimidine-5-carboxylate 200 mg (0.58 mmol) and 457 mg (1.74 mmol) triphenylphosphine in THF / DMF 1: 1 (16 mL) 229 μL (1.16 mmol) was added dropwise. 128 mg (1.16 mmol) of 4,6-difluoroindan-1-ol from Example 97A was added. The reaction mixture was warmed to room temperature and further stirred overnight. For workup, 5 mL of 1N hydrochloric acid was added with ice cooling and the mixture was stirred for an additional 15 minutes and then extracted with ethyl acetate. The organic phase was washed twice with 1N hydrochloric acid, twice with saturated sodium bicarbonate solution, then with saturated sodium chloride solution, then dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (Method 8). This gave 178 mg (61% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.01 min; m / z = 497 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 2.35-2.48 (m, 2H), 2.84-2.96 (m, 1H ), 3.02-3.16 (m, 1H), 3.31 (s, 3H), 3.37 (s, 3H), 4.18 (q, 2H), 6.25-6.55 ( m, 1H), 6.93-7.08 (m, 2H), 7.13-7.30 (m, 2H), 7.31-7.45 (m, 1H), 8.33 (s, 1H).

Example 107
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- (6-methyl-2,3-dihydro-1H-inden-1-yl) -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl (racemate)

  The title compound was prepared and purified as in Example 106. 1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 2A Starting from 200 mg (0.58 mmol) of ethyl-5-carboxylate and 112 mg (0.75 mmol) of 6-methylindan-1-ol from Example 100A, 130 mg (47% of theory) of the title compound were obtained. .

LC-MS (Method 1): Rt = 1.02 min; m / z = 475 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.21 (t, 3H), 2.25 (s, 3H), 2.31-2.43 (m, 2H), 2. 79-2.91 (m, 1H), 3.04-3.18 (m, 1H), 3.31 (s, 3H), 3.37 (s, 3H), 4.17 (q, 2H) 6.24-6.51 (m, 1H), 6.93-7.01 (m, 2H), 7.09 (d, 1H), 7.14-7.29 (m, 2H), 7 .31-7.47 (m, 1H), 8.31 (s, 1H).

Example 108
3- (4,6-Difluoro-2,3-dihydro-1H-inden-1-yl) -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazole-6 Yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

  The reaction time was 1 hour and 1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-1,2 from Example 31A. Starting with 200 mg (0.57 mmol) of ethyl 3,3,4-tetrahydropyrimidine-5-carboxylate and 127 mg (0.74 mmol) of 4,6-difluoroindan-1-ol from Example 97A In the same manner, the title compound was produced. The product was purified by preparative HPLC (Method 7). This gave 173 mg (57% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.10 min; m / z = 500 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 2.35-2.48 (m, 2H), 2.84-2.96 (m, 1H ), 3.00-3.15 (m, 1H), 3.44 (s, 3H), 4.18 (q, 2H), 6.27-6.52 (m, 1H), 6.93- 7.07 (m, 2H), 7.39-7.65 (m, 2H), 7.76-7.92 (m, 1H), 8.40 (s, 1H).

Example 109
3- (6-Methyl-2,3-dihydro-1H-inden-1-yl) -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl (racemate)

  The title compound was prepared and purified as in Example 108. 1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 31A Starting from 200 mg (0.57 mmol) of ethyl-5-carboxylate and 111 mg (0.74 mmol) of 6-methylindan-1-ol from Example 100A, 131 mg (47% of theory) of the title compound were obtained. .

LC-MS (Method 1): Rt = 1.11 min; m / z = 478 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 2.24 (s, 3H), 2.31-2.43 (m, 2H), 2. 79-2.91 (m, 1H), 3.01-3.17 (m, 1H), 3.44 (s, 3H), 4.17 (q, 2H), 6.21-6.51 ( m, 1H), 6.91-7.02 (m, 2H), 7.09 (d, 1H), 7.42 (d, 1H), 7.48-7.63 (m, 1H), 7 .77-7.92 (m, 1H), 8.38 (s, 1H).

Example 110
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [6-fluoro-4- (trifluoromethyl) -2,3-dihydro- 1H-Inden-1-yl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

  The title compound was prepared and purified as in Example 108. 1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 2A Starting from 60 mg (0.17 mmol) of ethyl-5-carboxylate and 50 mg (0.22 mmol) of 6-fluoro-4- (trifluoromethyl) indan-1-ol from Example 98A, 68 mg (theoretical) 71% of the amount).

LC-MS (Method 4): Rt = 2.38 min; m / z = 547 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.23 (t, 3H), 2.33-3.46 (m, 1H), 2.48-2.60 (m, 1H ), 2.95-3.07 (m, 1H), 3.26-3.40 (m, 7H), 4.21 (q, 2H), 6.47-6.57 (m, 1H), 6.86 (s, 1H), 6.92-7.01 (m, 3H), 7.08-7.17 (m, 1H), 8.24 (s, 1H).

Example 111
6- [5- (Ethoxycarbonyl) -2,4-dioxo-3-[(1R) -4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -3,4- Dihydropyrimidin-1 (2H) -yl] -3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate tert-butyl (R enantiomer)

  The title compound was prepared and purified as in Example 108, first with ice bath cooling. 6- [5- (Ethoxycarbonyl) -2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl] -3-methyl-2-oxo-2,3-dihydro- from Example 101A 2.50 g (5.80 mmol) tert-butyl 1H-benzimidazole-1-carboxylate and 1.29 g (6.39 mmol) 4- (trifluoromethyl) indan-1-ol (S enantiomer) from Example 14A Starting from 2,29 g (61% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.24 min; m / z = 615 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.21 (t, 3H), 1.56 (s, 9H), 2.35-2.43 (m, 1H), 2. 43-2.48 (m, 1H), 3.02-3.14 (m, 1H), 3.21-3.30 (m, 1H), 3.32 (br.s, 3H), 4. 18 (q, 2H), 6.33-6.59 (m, 1H), 7.26-7.45 (m, 3H), 7.46-7.58 (m, 2H), 7.77- 7.96 (m, 1H), 8.32 (s, 1H).

Example 112
1- (1-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [4- (trifluoromethyl) -2,3-dihydro- 1H-Inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer)

  2.29 g (3.73 mmol) of the compound from Example 111 was stirred in 50 mL of dichloromethane and 50 mL of trifluoroacetic acid at room temperature for 1 hour. The reaction mixture was concentrated to dryness on a rotary evaporator. The residue was mixed with ethyl acetate and 1M sodium carbonate solution. The organic phase was separated, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried under HV. This gave 1.66 g (84% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.03 min; m / z = 515 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 2.34-2.55 (m, 2H), 3.01-3.15 (m, 1H) ), 3.21-3.33 (m, 1H), 3.30 (s, 3H), 4.17 (q, 2H), 6.46 (br.m., 1H), 7.06-7 .23 (m, 2H), 7.36 (t, 1H), 7.45-7.55 (m, 2H), 8.31 (s, 1H), 11.12 (br.s, 1H).

Example 113
1- (3-Ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3-[(1R) -4- (trifluoromethyl ) -2,3-Dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer)

  First, 1- (1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [4- (trifluoromethyl) from Example 112. ) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer) 100 mg (0.19 mmol) in DMF (3 mL). I put it in. 36 mg (0.23 mmol) iodoethane and 126 mg (0.38 mmol) cesium carbonate were added. The reaction mixture was stirred at 60 ° C. for 1 hour. The reaction mixture was cooled to room temperature, filtered, and the filtrate was purified by preparative HPLC (Method 7). This gave 77 mg (72% of theory) of the title compound.

LC-MS (Method 4): Rt = 2.40 min; m / z = 543 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.22 (t, 6H), 2.31-2.45 (m, 1H), 2.45-2.56 (m, 1H ), 2.99-3.12 (m, 1H), 3.32 (s, 3H), 3.35-3.43 (m, 1H), 3.82 (q, 2H), 4.20 ( q, 2H), 6.48-6.59 (m, 1H), 6.88 (s, 1H), 6.91-6.98 (m, 2H), 7.17-7.29 (m, 2H), 7.41 (d, 1H), 8.24 (s, 1H).

Example 114
1- (3-Isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3-[(1R) -4- (trifluoromethyl ) -2,3-Dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer)

  The title compound was prepared and purified as in Example 113. 1- (1-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [4- (trifluoromethyl) -2 from Example 112 , 3-Dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer) 200 mg (0.30 mmol) and 2-iodopropane 79 mg (0.46 mmol) ) To give 125 mg (57% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.17 min; m / z = 557 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.23 (t, 3H), 1.40-1.44 (m, 6H), 2.31-2.43 (m, 1H ), 2.45-2.57 (m, 1H), 3.00-3.12 (m, 1H), 3.30 (s, 3H), 3.34-3.46 (m, 1H), 4.20 (q, 2H), 4.49-4.59 (m, 1H), 6.47-6.60 (m, 1H), 6.93 (s, 3H), 7.17-7. 28 (m, 2H), 7.41 (d, 1H), 8.23 (s, 1H).

Example 115
1- [1-Methyl-2-oxo-3- (3,3,3-trifluoro-2-hydroxypropyl) -2,3-dihydro-1H-benzimidazol-5-yl] -2,4-dioxo -3-[(1R) -4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (diastereo Mer mixture)

  The title compound was produced and purified in the same manner as in Example 113 with a reaction time of 16 hours. 1- (1-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [4- (trifluoromethyl) -2 from Example 112 , 3-Dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer) 250 mg (0.48 mmol) and 3-bromo-1,1,1 Starting from 112 mg (0.58 mmol) of trifluoropropan-2-ol (racemate), 186 mg (57% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.10 min; m / z = 627 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.23 (t, 3H), 2.28-2.43 (m, 1H), 2.44-2.57 (m, 1H ), 2.98-3.12 (m, 1H), 3.33-3.44 (m, 4H), 4.00-4.10 (m, 1H), 4.11-4.24 (m) 3H), 4.25-4.47 (m, 2H), 6.47-6.60 (m, 1H), 6.94-7.06 (m, 3H), 7.17-7.29. (M, 2H), 7.41 (d, 1H), 8.21 (s, 1H).

Example 116
1- [1-Methyl-2-oxo-3- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-benzimidazol-5-yl] -2,4-dioxo-3- [ (1R) -4- (Trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer)

  1- (1-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [4- (4- (Example 1) in 7.5 mL of DMF. (Trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer) 250 mg (0.48 mmol), cesium carbonate 317 mg (0.97 mmol), 2 mg (12 μmol) of potassium iodide and 103 mg (0.58 mmol) of 3-bromo-1,1,1-trifluoropropane were stirred at 60 ° C. Due to insufficient conversion after 16 hours, an additional 1 eq each of cesium carbonate and 3-bromo-1,1,1-trifluoropropane was added after 16 hours and again after 40 hours the mixture was heated to 60 ° C. And stirred overnight. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and washed twice with 1N hydrochloric acid. The organic phase was dehydrated with sodium sulfate and the solvent was removed on a rotary evaporator. The residue was stirred in MTBE and the solid formed was filtered off with suction. The solid was an unreacted reactant (88 mg). The filtrate was concentrated and the residue was purified by preparative HPLC (Method 7). This gave 106 mg (35% of theory) of the title compound.

LC-MS (Method 5): Rt = 1.19 min; m / z = 611 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 2.36-2.44 (m, 1H), 2.44-2.48 (m, 1H) ) 2.69-2.82 (m, 2H), 3.03-3.15 (m, 1H), 3.23-3.30 (m, 1H), 3.37 (s, 3H), 4.10 (t, 2H), 4.18 (q, 2H), 6.36-6.55 (m, 1H), 7.17-7.32 (m, 2H), 7.37 (t, 1H), 7.45-7.51 (m, 2H), 7.51-7.56 (m, 1H), 8.35 (s, 1H).

Example 117
1- (3-Cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3-[(1R) -4- (trifluoro Methyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer)

  100 mg (0.19 mmol) of the compound from Example 112, 33.4 mg (0.39 mmol) of cyclopropylboronic acid, 24 mg (0.19 mmol) of copper (I) acetate, 41.2 mg (0.39 mmol) of sodium carbonate, pyridine A mixture of 31 μL (0.39 mmol) of toluene (2 mL) was stirred at 70 ° C. for 6 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and washed twice with 1N hydrochloric acid. The organic phase was dehydrated with sodium sulfate and the solvent was removed on a rotary evaporator. The residue was purified by preparative HPLC (Method 8). This gave 90 mg (84% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.09 min; m / z = 555 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 0.92-1.01 (m, 2H), 1.04-1.11 (m, 2H), 1.31 (t, 3H ), 2.39-2.51 (m, 1H), 2.53-2.65 (m, 1H), 2.86 (br.spt, 1H), 3.08-3.21 (m, 1H ), 3.36 (s, 3H), 3.42-3.55 (m, 1H), 4.29 (q, 2H), 6.55-6.68 (m, 1H), 6.96- 7.05 (m, 2H), 7.11-7.16 (m, 1H), 7.27-7.32 (m, 1H), 7.33 (d, 1H), 7.49 (d, 1H), 8.32 (s, 1H).

Example 118
1- [3- (Cyanomethyl) -1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] -2,4-dioxo-3-[(1R) -4- (tri Fluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer)

  First, 1- (1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [4- (trifluoromethyl) from Example 112. ) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (R enantiomer) 200 mg (0.38 mmol) in acetonitrile (3.7 mL) ), 93 mg (0.77 mmol) of bromoacetonitrile and 161 mg (1.16 mmol) of potassium carbonate were added. The reaction mixture was stirred at 70 ° C. for 2 hours. The reaction mixture cooled to room temperature was mixed with 3 mL of 1N hydrochloric acid and stirred for 10 minutes. The entire mixture was separated directly by preparative HPLC (Method 7). This gave 180 mg (83% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.09 min; m / z = 554 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 2.38-2.47 (m, 2H), 3.03-3.15 (m, 1H) ), 3.23-3.28 (m, 1H), 3.40 (s, 3H), 4.17 (q, 2H), 5.13 (s, 2H), 6.35-6.56 ( m, 1H), 7.26-7.40 (m, 3H), 7.46-7.61 (m, 3H), 8.36 (s, 1H).

Example 119
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-3- [7- (trifluoromethyl) -2,3- Dihydro-1-benzofur-3-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

  The title compound was prepared and purified as in Example 108. 1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 31A From 71 mg (0.20 mmol) of ethyl-5-carboxylate and 50 mg (0.24 mmol) of 7- (trifluoromethyl) -2,3-dihydro-1-benzofuran-3-ol (racemic) from Example 99A Starting from 35 mg (31% of theory) of the title compound.

LC-MS (Method 4): Rt = 2.35 min; m / z = 534 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.24 (t, 3H), 3.37 (s, 3H), 4.22 (q, 2H), 4.69-4. 75 (m, 1H), 4.79 (t, 1H), 6.75-6.82 (m, 1H), 6.87 (t, 1H), 7.05 (d, 1H), 7.22 (Dd, 1H), 7.30 (d, 1H), 7.33-7.38 (m, 2H), 8.21 (s, 1H).

Example 120
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- (5-methoxy-2,3-dihydro-1H-inden-1-yl) -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl (racemate)

  First, under an argon atmosphere, 200 mg (0.58 mmol) of the compound from Example 2A and 457 mg (1.74 mmol) of triphenylphosphine were placed in 8 mL of DMF and 8 mL of THF and cooled to −40 ° C. 229 μL (1.16 mmol) of diisopropyl azodicarboxylate and then 155 mg (80% purity, 0.76 mmol) of the compound from Example 102A were added dropwise. The cooling bath was removed and the mixture was stirred at room temperature overnight. Then 25 mL of 1N hydrochloric acid was added and the mixture was stirred for an additional 15 minutes. For workup, 5 mL of 1N hydrochloric acid was added to the reaction mixture with ice cooling, and the mixture was stirred for an additional 15 minutes and then extracted with ethyl acetate. The organic phase was washed twice with 1N hydrochloric acid, twice with saturated sodium bicarbonate solution, then with saturated sodium chloride solution, then dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (Method 7). This gave 89 mg (30% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.96 min; m / z = 491 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 2.24 to 2.48 (m, 2H), 2.80 to 2.96 (m, 1H) ), 3.09-3.21 (m, 1H), 3.31 (s, 3H), 3.36 (s, 3H), 3.72 (s, 3H), 4.17 (q, 2H) 6.25-6.48 (m, 1H), 6.69 (dd, 1H), 6.78 (s, 1H), 7.04 (d, 1H), 7.10-7.29 (m 2H), 7.37 (br.s, 1H), 8.30 (s, 1H).

Example 121
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  First, 1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) from Example 1. ) -Benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (5.60 g, 10.84 mmol) was placed in glacial acetic acid (78 mL) and concentrated hydrochloric acid (39 mL) at 120 ° C. Stir for 1 hour. The mixture was then cooled to room temperature and mixed with water, and the precipitate was filtered off with suction. The solid was washed sequentially with water and MTBE and then dried at 50 ° C. under reduced pressure. This gave 5.11 g (96% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.98 min; m / z = 489 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.47 (s, 3H), 3.31 (s, 3H), 3.37 (s, 3H), 5.11 (s, 2H), 7.22-7.30 (m, 2H), 7.33-7.43 (m, 3H), 7.59-7.63 (m, 1H), 8.45 (s, 1H) 12.73 (br.s, 1H).

Example 122
3- [2,3-Bis (trifluoromethyl) benzyl] -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was prepared and purified as in Example 121. 3- [2,3-Bis (trifluoromethyl) benzyl] -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-from Example 8 Starting from 114 mg (0.20 mmol) of ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 92 mg (85% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.01 min; m / z = 543 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.34 (s, 3H), 3.37 (s, 3H), 5.27 (m, 2H), 7.22-7. 30 (m, 2H), 7.37-7.40 (m, 1H), 7.73-7.77 (m, 1H), 7.82-7.88 (m, 1H), 7.96- 8.00 (m, 1H), 8.47 (s, 1H), 12.73 (br.s, 1H).

Example 123
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was prepared and purified as in Example 121. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) from Example 2 Starting from 200 mg (0.37 mmol) of ethyl -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 67 mg (88% of theory) of the title compound were obtained.

LC-MS (Method 3): Rt = 1.21 min; m / z = 509 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.34 (s, 3H), 3.37 (s, 3H), 5.18 (s, 2H), 7.22-7. 30 (m, 2H), 7.38-7.41 (m, 1H), 7.51-7.57 (m, 1H), 7.58-7.63 (m, 1H), 7.78- 7.83 (m, 1H), 8.47 (s, 1H), 12.72 (br.s, 1H).

Example 124
3- (2,3-Dichlorobenzyl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2, 3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- (2,3-Dichlorobenzyl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo from Example 3 Starting from 200 mg (0.40 mmol) of ethyl -1,2,3,4-tetrahydropyrimidine-5-carboxylate, 147 mg (78% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.00 min; m / z = 475 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.34 (s, 3H), 3.37 (s, 3H), 5.13 (s, 2H), 7.22-7. 30 (m, 3H), 7.31-7.37 (m, 1H), 7.38-7.41 (m, 1H), 7.57-7.61 (m, 1H), 8.45 ( s, 1H), 12.72 (br.s, 1H).

Example 125
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [3-fluoro-2- (trifluoromethyl) benzyl] -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [3-fluoro-2- (trifluoromethyl) benzyl] from Example 5 Starting from 170 mg (0.33 mmol) of ethyl -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 141 mg (87% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.98 min; m / z = 493 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.34 (s, 3H), 3.37 (s, 3H), 5.22 (s, 2H), 7.19-7. 30 (m, 3H), 7.36-7.45 (m, 2H), 7.63-7.71 (m, 1H), 8.47 (s, 1H), 12.71 (br.s, 1H).

Example 126
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-fluoro-3- (trifluoromethyl) benzyl] -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-fluoro-3- (trifluoromethyl) benzyl] from Example 4 Starting from 161 mg (0.31 mmol) of ethyl -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 115 mg (76% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.98 min; m / z = 493 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.34 (s, 3H), 3.36-3.39 (m, 3H), 5.17 (s, 2H), 7. 21-7.29 (m, 2H), 7.38 (s, 2H), 7.65-7.74 (m, 2H), 8.42 (s, 1H), 12.72 (br.s, 1H).

Example 127
3- (2-Chloro-3,6-difluorobenzyl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was produced and purified in the same manner as in Example 121, with the reaction time being 30 minutes. 3- (2-Chloro-3,6-difluorobenzyl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2 from Example 6 Starting from 110 mg (0.22 mmol) of ethyl 1,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 80 mg (76% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.93 min; m / z = 477 (M + H) ^<+> .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.2-3.4 (2 s, hidden by water signal), 5.24 (s, 2H), 7.14-7 .19 (m, 1H), 7.23-7.32 (m, 2H), 7.32-7.36 (m, 1H), 7.40-7.48 (m, 1H), 8.39 (S, 1H), 12.74 (br.s, 1H).

Example 128
3- (3-Chloro-2-methylbenzyl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1, 2,3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was produced and purified in the same manner as in Example 121, with the reaction time being 30 minutes. 3- (3-Chloro-2-methylbenzyl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4 from Example 7 Starting from 75 mg (0.16 mmol) of ethyl dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 62 mg (87% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.96 min; m / z = 455 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.41 (s, 3H), 3.34 (s, 3H), 3.37 (s, 3H), 5.08 (s, 2H), 7.06-7.09 (m, 1H), 7.17 (t, 1H), 7.22-7.29 (m, 2H), 7.33-7.37 (m, 1H) 7.39-7.42 (m, 1H), 8.44 (s, 1H), 12.73 (br.s, 1H).

Example 129
3- (3-Chloro-5-fluorobenzyl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1, 2,3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was prepared and purified as in Example 121. The reaction time was 45 minutes. 3- (3-Chloro-5-fluorobenzyl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4 from Example 9 Starting from 244 mg (0.50 mmol) of ethyl dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 198 mg (85% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.98 min; m / z = 459 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.31 (s, 3H), 3.37 (s, 3H), 5.02 to 5.09 (m, 2H), 7. 19-7.33 (m, 4H), 7.33-7.38 (m, 1H), 7.39 (s, 1H), 8.39 (s, 1H), 12.73 (s, 1H) .

Example 130
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [3-fluoro-5- (trifluoromethyl) benzyl] -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was prepared and purified as in Example 121. The reaction time was 45 minutes. 1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [3-fluoro-5- (trifluoromethyl) benzyl] from Example 10 Starting from 268 mg (0.51 mmol) of ethyl -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 215 mg (84% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.00 min; m / z = 493 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.31 (s, 3H), 3.37 (s, 3H), 5.15 (s, 2H), 7.23 (dd, 1H), 7.28 (d, 1H), 7.38 (d, 1H), 7.54 (d, 1H), 7.58-7.65 (m, 2H), 8.40 (s, 1H) ), 12.73 (s, 1H).

Example 131
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [4- (trifluoromethyl) -2,3- Dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemic)

  First, 1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [4- (tri Fluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate 103 mg (0.19 mmol) in acetonitrile / water 1.5: 1 (2.5 mL), sodium bicarbonate 36 mg (0.43 mmol) was added and the mixture was stirred at 80 ° C. for 4 h. The cooled reaction mixture was acidified with 1N hydrochloric acid and extracted twice with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was separated by HPLC (Method 7). The product fraction was almost completely concentrated on a rotary evaporator and the precipitated solid was filtered and dried with a high vacuum pump. This gave 32 mg (33% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.01 min; m / z = 501 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.39-2.46 (m, 1H), 2.46-2.48 (m, 1H, partially hidden by DMSO signal 3.04-3.16 (m, 1H), 3.23-3.29 (m, 1H, partly hidden by water signal), 3.31 (s, 3H), 3.35-3.38 (m, 3H), 6.36-6.60 (m, 1H), 7.13-7.29 (m, 2H), 7.31-7.42 (m, 2H) ), 7.49-7.57 (m, 2H), 8.38 (s, 1H), 12.70 (br.s, 1H).

Example 132
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3-[(1R) -4- (trifluoromethyl)- 2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (R enantiomer)

  1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [4- (trifluoromethyl) from Example 13 -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate 4.20 g (7.79 mmol) together with 40 mL of glacial acetic acid and 20 mL of concentrated hydrochloric acid. Stir at reflux temperature for 1 hour. The reaction mixture was cooled to room temperature, then the precipitated solid diluted with 300 mL of water was filtered off with suction, washed with a little water and dried under HV. The solid thus obtained was stirred with 45 mL of toluene. Initially it dissolved completely, but after a few minutes a crystalline solid formed. The mixture was cooled to 0 ° C. and stirred at this temperature for 30 minutes. The solid was then filtered, washed with 5 mL of toluene and dried under HV. This gave 3.17 g (81% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.06 min; m / z = 501 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.38-2.46 (m, 1H), 2.46-2.60 (m, 1H; partially hidden under DMSO signal 3.10 (dt, 1H), 3.23-3.35 (m, 1H; partially hidden under DMSO signal), 3.31 (s, 4H), 3.36 ( s, 3H), 6.36-6.60 (m, 1H), 7.12-7.30 (m, 2H), 7.31-7.43 (m, 2H), 7.48-7. 58 (m, 2H), 8.38 (s, 1H), 12.71 (br.s, 1H).

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 2.42 to 2.53 (m, 1H), 2.60 to 2.72 (m, 1H), 3.11 to 3.25 (M, 1H), 3.39 (s, 3H), 3.41 (s, 3H), 3.45-3.55 (m, 1H), 6.59-6.71 (m, 1H), 6.94 (br.s, 1H), 7.04 (s, 2H), 7.28-7.41 (m, 2H), 7.54 (d, 1H), 8.57 (s, 1H) 12.45 (br.s, 1H).

In a similar experiment, a fraction with 99% purity could be isolated. For this batch, the measured specific rotations were as follows:

Specific rotation: α _D ²⁰ = + 110.6 °, (methanol, c = 0.405 g / 100 mL).

  X-ray structural analysis in a complex with chymase confirmed the R configuration for this enantiomer.

Example 133
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3-[(1S) -4- (trifluoromethyl)- 2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (S enantiomer)

  5.10 g (9.65 mmol) of the compound from Example 12 was stirred in refluxing temperature for 15 minutes in 50 mL of glacial acetic acid and 25 mL of concentrated hydrochloric acid. After cooling to room temperature, the mixture was diluted with 5 mL of acetonitrile and separated in small portions by preparative HPLC (Method 7). This gave 4.5 g (93% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.02 min; m / z = 501 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 2.33-2.46 (m, 1H), 2.58 (dtd, 1H), 3.04-3.16 (m, 1H) ), 3.30 (s, 3H), 3.33 (s, 3H), 3.36-3.47 (m, 1H), 6.50-6.66 (m, 1H), 6.86 ( br.s, 1H), 6.95 (br.s, 2H), 7.20-7.33 (m, 2H), 7.46 (d, 1H), 8.49 (s, 1H), 12 .38 (br.s, 1H).

Example 134
1- (6-Fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3-[(1R) -4- (tri Fluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (R enantiomer)

  The title compound was prepared and purified in the same manner as in Example 121 with a reaction time of 45 minutes. 1- (6-Fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [4- (from Example 104 Starting from 120 mg (0.22 mmol) of ethyl (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (method After further purification by 8), 92 mg (80% of theory) of the title compound were obtained.

LC-MS (Method 5): Rt = 1.09 min; m / z = 519 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 2.31-2.43 (m, 1H), 2.51-2.62 (m, 1H), 3.03-3.14 (M, 1H), 3.28 (s, 3H), 3.29 (s, 3H), 3.34-3.47 (m, 1H), 6.50-6.58 (m, 1H), 6.76-6.84 (m, 2H), 7.21-7.27 (m, 2H), 7.41-7.47 (m, 1H), 8.41 (s, 1H), 12. 31 (s, 1H).

Example 135
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) from Example 21 Starting from 170 mg (0.30 mmol) of ethyl -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 133 mg (82% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.20 min; m / z = 537 (M + H) ^<+> .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 6H), 3.82-3.96 (m, 4H), 5.18 (s, 2H), 7. 21-7.27 (m, 1H), 7.34 (d, 1H), 7.43-7.48 (m, 1H), 7.50-7.63 (m, 2H), 7.77- 7.84 (m, 1H), 8.50 (s, 1H), 12.71 (br.s, 1H).

Example 136
1- (1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 1- (1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) -benzyl from Example 22 Starting from 170 mg (0.31 mmol) of ethyl 2,2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 144 mg (89% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.10 min; m / z = 517 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 6H), 2.47 (s, 3H), 3.84-3.95 (m, 4H), 5. 12 (s, 2H), 7.22-7.26 (m, 1H), 7.33 (s, 3H), 7.46-7.48 (m, 1H), 7.59-7.63 ( m, 1H), 8.49 (s, 1H), 12.72 (br.s, 1H).

Example 137
3- (2,3-Dichlorobenzyl) -1- (1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2, 3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- (2,3-Dichlorobenzyl) -1- (1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo from Example 23 Starting from 244 mg (0.46 mmol) of ethyl -1,2,3,4-tetrahydropyrimidine-5-carboxylate, 188 mg (81% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.08 min; m / z = 503 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 6H), 3.83-3.95 (m, 4H), 5.14 (s, 2H), 7. 21-7.27 (m, 2H), 7.31-7.37 (m, 2H), 7.45-7.47 (m, 1H), 7.57-7.61 (m, 1H), 8.49 (s, 1H), 12.71 (br.s, 1H).

Example 138
1- (1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [3-fluoro-2- (trifluoromethyl) benzyl] -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 1- (1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [3-fluoro-2- (trifluoromethyl) benzyl] from Example 24 Starting from 167 mg (0.30 mmol) of ethyl -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 96 mg (61% of theory) of the title compound were obtained.

LC-MS (Method 3): Rt = 1.24 min; m / z = 521 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 6H), 3.83-3.96 (m, 4H), 5.23 (s, 2H), 7. 19-7.26 (m, 2H), 7.31-7.37 (m, 1H), 7.37-7.48 (m, 2H), 7.63-7.72 (m, 1H), 8.50 (s, 1H), 12.71 (br.s, 1H).

Example 139
3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2, 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5 from Example 18 Yl) Starting from 73 mg (0.13 mmol) of ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 50 mg (69% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.08 min; m / z = 523 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 3.37 (s, 3H), 3.88 (q, 2H), 5.21-5. 27 (m, 2H), 7.21-7.30 (m, 2H), 7.33-7.37 (m, 1H), 7.43-7.46 (m, 1H), 7.58- 7.68 (m, 2H), 8.49 (s, 1H), 12.72 (br.s, 1H).

Example 140
3- [2-chloro-3- (trifluoromethyl) benzyl] -1- (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2, 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5 from Example 19 Yl) Starting from 75 mg (0.14 mmol) of ethyl 2,2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 35 mg (49% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.02 min; m / z = 523 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 3.37 (s, 3H), 3.88 (q, 2H), 5.18 (s, 2H), 7.22-7.30 (m, 2H), 7.44-7.47 (m, 1H), 7.51-7.57 (m, 1H), 7.58-7.62 ( m, 1H), 7.79-7.83 (m, 1H), 8.49 (s, 1H), 12.73 (br.s, 1H).

Example 141
1- (3-Ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) -benzyl] -2 , 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 1- (3-Ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) from Example 20 Starting from 53 mg (0.10 mmol) of ethyl [benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 23 mg (46% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.06 min; m / z = 503 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 2.47 (s, 3H), 3.37 (s, 3H), 3.87 (q, 2H), 5.11 (s, 2H), 7.22-7.30 (m, 2H), 7.33-7.43 (m, 2H), 7.46-7.49 (m, 1H) , 7.59-7.64 (m, 1H), 8.48 (s, 1H), 12.74 (br.s, 1H).

Example 142
3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- [1-methyl-2-oxo-3- (2,2,2-trifluoroethyl) -2,3-dihydro-1H- Benzimidazol-5-yl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- [1-methyl-2-oxo-3- (2,2,2-trifluoroethyl) -2,3 from Example 25 Starting from 90 mg (0.15 mmol) of ethyl dihydro-1H-benzimidazol-5-yl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 61% of theory) was obtained.

LC-MS (Method 1): Rt = 1.12 min; m / z = 577 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.41 (s, 3H), 4.81 (q, 2H), 5.22-5.26 (m, 2H), 7. 30-7.39 (m, 3H), 7.51-7.55 (m, 1H), 7.57-7.67 (m, 2H), 8.46 (s, 1H), 12.74 ( br.s, 1H).

Example 143
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- [1-methyl-2-oxo-3- (2,2,2-trifluoroethyl) -2,3-dihydro-1H- Benzimidazol-5-yl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- [1-methyl-2-oxo-3- (2,2,2-trifluoroethyl) -2,3 from Example 26 Starting from 80 mg (0.13 mmol) of ethyl dihydro-1H-benzimidazol-5-yl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 57% of theory) was obtained.

LC-MS (Method 1): Rt = 1.12 min; m / z = 577 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.41 (s, 3H), 4.80 (q, 2H), 5.17 (s, 2H), 7.31-7. 38 (m, 2H), 7.50-7.56 (m, 2H), 7.59-7.63 (m, 1H), 7.79-7.83 (m, 1H), 8.45 ( s, 1H), 12.75 (br.s, 1H).

Example 144
1- [1-Methyl-2-oxo-3- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3- [2-methyl-3- (Trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 1- [1-Methyl-2-oxo-3- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3- [2 from Example 27 Starting from 41 mg (0.07 mmol) of ethyl 3-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 63% of theory) was obtained.

LC-MS (Method 3): Rt = 1.33 min; m / z = 557 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.47 (s, 3H), 3.41 (s, 3H), 4.80 (q, 2H), 5.11 (s, 2H), 7.31-7.43 (m, 4H), 7.55 (s, 1H), 7.58-7.63 (m, 1H), 8.43 (s, 1H), 12.76. (Br.s, 1H).

Example 145
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- [3- (cyclopropylmethyl) -1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl ] -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- [3- (cyclopropylmethyl) -1-methyl-2-oxo-2,3-dihydro-1H-benzen from Example 29 Imidazol-5-yl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate starting from 65 mg (0.11 mmol) in the same manner as in Example 121, the title compound Was prepared and purified. The resulting crude product was further purified by preparative HPLC (Method 22). This gave 23 mg (62% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.08 min; m / z = 549 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.35-0.49 (m, 4H), 1.14-1.26 (m, 1H), 2.5 (s, DMSO (Hidden by signal) 3.38 (s, 3H), 3.72 (d, 2H), 5.18 (s, 2H), 7.22-7.31 (m, 2H), 7.50 -7.57 (m, 2H), 7.58-7.63 (m, 1H), 7.79-7.83 (m, 1H), 8.48 (s, 1H), 12.73 (br) .S, 1H).

Example 146
1- [3- (Cyclopropylmethyl) -1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] -3- [2-methyl-3- (trifluoromethyl) benzyl ] -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was prepared and purified as in Example 121. 1- [3- (Cyclopropylmethyl) -1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] -3- [2-methyl-3- (from Example 30 Further purification by preparative HPLC (Method 10) starting from 69 mg (0.12 mmol) of ethyl (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 29 mg (90%, 40% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.08 min; m / z = 529 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.35 to 0.41 (m, 2H), 0.42 to 0.49 (m, 2H), 1.15 to 1.25 (M, 1H), 2.47 (s, 3H), 3.38 (s, hidden by DMSO signal), 3.72 (d, 2H), 5.12 (s, 2H), 7.23 -7.30 (m, 2H), 7.33-7.43 (m, 2H), 7.51-7.54 (m, 1H), 7.59-7.63 (m, 1H), 8 .47 (s, 1H), 12.73 (br.s, 1H).

Example 147
3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- [3- (cyclopropylmethyl) -1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl ] -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- [3- (cyclopropylmethyl) -1-methyl-2-oxo-2,3-dihydro-1H-benzen from Example 31 Starting from 115 mg (0.23 mmol) of ethyl imidazol-5-yl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 92 mg (84% of theory) of the title compound Got.

LC-MS (Method 1): Rt = 1.13 min; m / z = 549 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.35-0.41 (m, 2H), 0.41-0.49 (m, 2H), 1.15-1.25 (M, 1H), 3.4 (s, hidden by water signal), 3.72 (d, 2H), 5.25 (br.s, 2H), 7.22-7.31 (m 2H), 7.32-7.38 (m, 1H), 7.49-7.52 (m, 1H), 7.57-7.68 (m, 2H), 8.48 (s, 1H) ), 12.73 (br.s, 1H).

Example 148
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- [1-methyl-3- (oxetan-2-ylmethyl) -2-oxo-2,3-dihydro-1H-benzimidazole-5 -Yl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemic)

  In the same manner as in Example 121, the title compound was produced and purified. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- [1-methyl-3- (oxetan-2-ylmethyl) -2-oxo-2,3-dihydro-1H from Example 32 -Benzimidazol-5-yl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 56 mg (0.09 mmol), 10 mg of the title compound (theoretical 18 %).

LC-MS (Method 3): Rt = 1.24 min; m / z = 565 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.11-2.21 (m, 1H), 2.26-2.36 (m, 1H), 3.36 (s, 3H ), 3.72 (q, 1H), 3.84-3.91 (m, 1H), 3.93-3.99 (m, 1H), 4.11-4.18 (m, 1H), 5.09-5.20 (m, 3H), 7.25-7.32 (m, 2H), 7.43-7.46 (m, 1H), 7.50-7.57 (m, 1H) ), 7.60-7.65 (m, 1H), 7.78-7.84 (m, 1H), 8.48 (s, 1H), 12.74 (br.s, 1H).

Example 149
1- (3-cyclobutyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2, 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was prepared and purified in the same manner as in Example 121 at 60 ° C. with a reaction time of 5.5 hours. 1- (3-Cyclobutyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) from Example 33 Starting from 33 mg (0.06 mmol) of ethyl [benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 18 mg (57% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.10 min; m / z = 529 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.73-1.90 (m, 2H), 2.21-2.31 (m, 2H), 2.47 (s, part 2.75-2.87 (m, 2H), 3.34 (s, partially hidden by water signal), 4.78-4.89 (hidden by DMSO signal) m, 1H), 5.12 (s, 2H), 7.24-7.29 (m, 2H), 7.34-7.39 (m, 1H), 7.40-7.44 (m, 1H), 7.59-7.63 (m, 1H), 7.64-7.67 (m, 1H), 8.49 (s, 1H), 12.73 (br.s, 1H).

Example 150
1- (3-Cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2 , 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  The reaction time was 2 hours, and the title compound was produced and purified in the same manner as in Example 121 at 60 ° C. 1- (3-Cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) from Example 35 Starting from 141 mg (0.26 mmol) of ethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 107 mg (80% of theory) of the title compound were obtained. .

LC-MS (Method 5): Rt = 1.07 min; m / z = 515 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.86-0.92 (m, 2H), 0.99-1.05 (m, 2H), 2.47 (s, part 2.88-2.95 (m, 1H), 3.31 (s, partly hidden by water signal), 5.11 (s, 2H) 7.25 (s, 2H), 7.33-7.39 (m, 1H), 7.40-7.47 (m, 2H), 7.59-7.63 (m, 1H), 8 .45 (s, 1H), 12.72 (br.s, 1H).

Example 151
1- (3-Isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2, 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was prepared and purified in the same manner as in Example 121 at 60 ° C. with a reaction time of 5.5 hours. 1- (3-Isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) from Example 34 Starting from 33 mg (0.06 mmol) of ethyl [benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 25 mg (76% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.06 min; m / z = 517 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.44 (d, 6H), 2.47 (s, partially hidden by the DMSO signal), 3.35 (s, 4.55-4.64 (m, 1H), 5.12 (s, 2H), 7.21-7.28 (m, 2H), 7.33 -7.43 (m, 2H), 7.58-7.63 (m, 2H), 8.47 (s, 1H), 12.73 (br.s, 1H).

Example 152
1- [3-Methyl-2-oxo-1- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3- [2-methyl-3- (Trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 1- [3-Methyl-2-oxo-1- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3- [2 from Example 38 Starting from 57 mg (0.09 mmol) of ethyl -methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 48 mg (0.09 mmol) 83% of theory) was obtained.

LC-MS (Method 1): Rt = 1.08 min; m / z = 557 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.47 (s, 3H), 3.37 (s, 3H), 4.85 (q, 2H), 5.11 (s, 2H), 7.30 (dd, 1H), 7.33-7.45 (m, 3H), 7.47-7.50 (m, 1H), 7.59-7.63 (m, 1H) 8.49 (s, 1H), 12.73 (br.s, 1H).

Example 153
1- [1- (Cyclopropylmethyl) -3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] -3- [2-methyl-3- (trifluoromethyl) benzyl ] -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was prepared and purified as in Example 121. 1- [1- (Cyclopropylmethyl) -3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl] -3- [2-methyl-3- (from Example 39 Trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate starting from 52 mg (0.09 mmol) and purification by HPLC (Method 8) After additional precision purification by HPLC (Method 23), 19 mg (37% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.09 min; m / z = 529 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.36-0.42 (m, 2H), 0.44-0.50 (m, 2H), 1.15-1.25 (M, 1H), 2.47 (s, 3H), 3.35 (br.s, 3H, partly hidden by water signal), 3.77 (d, 2H), 5.11 ( s, 2H), 7.24 (dd, 1H), 7.33-7.43 (m, 4H), 7.61 (d, 1H), 8.47 (s, 1H), 12.72 (s) 1H).

Example 154
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-1H-benzotriazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-1H-benzotriazol-5-yl) -2,4-dioxo-1,2,3 from Example 71 Starting from 149 mg (0.29 mmol) of ethyl 1,4-tetrahydropyrimidine-5-carboxylate, 115 mg (80% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.03 min; m / z = 480 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 4.37 (s, 3H), 5.19 (s, 2H), 7.51 to 7.58 (m, 1H), 7. 62-7.67 (m, 1H), 7.73 (dd, 1H), 7.79-7.84 (m, 1H), 8.00 (d, 1H), 8.30-8.33 ( m, 1H), 8.62 (s, 1H), 12.76 (br.s, 1H).

Example 155
1- (1-Methyl-1H-benzotriazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 1- (1-Methyl-1H-benzotriazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3 from Example 72 Starting from 151 mg (0.31 mmol) of ethyl 1,4-tetrahydropyrimidine-5-carboxylate, 124 mg (86% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.02 min; m / z = 460 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.47 (s, 3H), 4.37 (s, 3H), 5.12 (s, 2H), 7.33-7. 40 (m, 1H), 7.42-7.48 (m, 1H), 7.59-7.64 (m, 1H), 7.70-7.76 (m, 1H), 8.00 ( d, 1H), 8.31-8.35 (m, 1H), 8.61 (s, 1H), 12.75 (br.s, 1H).

Example 156
3- (2,3-Dichlorobenzyl) -1- (1-methyl-1H-benzotriazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- (2,3-Dichlorobenzyl) -1- (1-methyl-1H-benzotriazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 73 Starting from 188 mg (0.40 mmol) of ethyl 5-carboxylate, 143 mg (80% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.00 min; m / z = 446 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 4.37 (s, 3H), 5.14 (s, 2H), 7.27-7.31 (m, 1H), 7. 32-7.38 (m, 1H), 7.56-7.62 (m, 1H), 7.70-7.74 (m, 1H), 8.00 (d, 1H), 8.30- 8.33 (m, 1H), 8.61 (s, 1H), 12.75 (br.s, 1H).

Example 157
3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- (1-methyl-1H-benzotriazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- (1-methyl-1H-benzotriazol-5-yl) -2,4-dioxo-1,2,3 from Example 74 Starting from 115 mg (0.31 mmol) of ethyl 1,4-tetrahydropyrimidine-5-carboxylate, 92 mg (84% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.03 min; m / z = 480 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 4.37 (s, 3H), 5.22-5.28 (m, 2H), 7.37-7.42 (m, 1H ), 7.58-7.68 (m, 2H), 7.69-7.74 (m, 1H), 8.00 (d, 1H), 8.29-8.33 (m, 1H), 8.63 (s, 1H), 12.75 (br.s, 1H).

Example 158
1- (1-Methyl-1H-indazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 1- (1-Methyl-1H-indazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3 from Example 75 Starting from 254 mg (0.52 mmol) of ethyl 4-tetrahydropyrimidine-5-carboxylate, 212 mg (88% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.04 min; m / z = 459 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.47 (s, 3H), 4.10 (s, 3H), 5.12 (s, 2H), 7.33-7. 39 (m, 1H), 7.41-7.46 (m, 1H), 7.52-7.56 (m, 1H), 7.59-7.63 (m, 1H), 7.76- 7.80 (m, 1H), 7.97-7.99 (m, 1H), 8.16-8.19 (m, 1H), 8.52 (s, 1H), 12.72 (br. s, 1H).

Example 159
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-1H-benzimidazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-carboxylic acid

  3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-1H-benzimidazole from Example 82 in 1.5 mL of glacial acetic acid / concentrated hydrochloric acid 2: 1 (volume ratio). 94 mg (0.18 mmol) of ethyl 6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate was heated to 120 ° C. for 30 minutes. The cooled reaction mixture was mixed with water and extracted twice with dichloromethane, and the combined organic phases were dried over magnesium sulfate and concentrated. The residue was stirred with ethyl acetate and the precipitated solid was filtered off with suction and dried at 50 ° C. under reduced pressure. This gave 88 mg (98% of theory) of the title compound.

LC-MS (Method 3): Rt = 1.12 min; m / z = 479 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 4.00 (s, 3H), 5.19 (s, 2H), 7.54 (t, 1H), 7.59-7. 67 (m, 2H), 7.81 (d, 1H), 7.92 (d, 1H), 8.10 (s, 1H), 8.56 (s, 1H), 9.13 (s, 1H) ).

Example 160
1- (1-Methyl-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 1- (1-Methyl-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3 from Example 77 Starting from 170 mg (0.35 mmol) of ethyl 1,4-tetrahydropyrimidine-5-carboxylate, 124 mg (77% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.90 min; m / z = 459 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.47 (s, 3H), 3.89 (s, 3H), 5.12 (s, 2H), 7.33-7. 40 (m, 1H), 7.41-7.46 (m, 2H), 7.59-7.63 (m, 1H), 7.71 (d, 1H), 7.86-7.89 ( m, 1H), 8.33 (s, 1H), 8.50 (s, 1H), 12.72 (br.s, 1H).

Example 161
3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- (1-methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- (1-methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3 from Example 78 Starting from 82 mg (0.16 mmol) of ethyl 1,4-tetrahydropyrimidine-5-carboxylate, 52 mg (66% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.93 min; m / z = 479 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.89 (s, 3H), 5.25 (br.s, 2H), 7.35-7.46 (m, 2H), 7.58-7.68 (m, 2H), 7.71 (d, 1H), 7.84-7.88 (m, 1H), 8.33 (s, 1H), 8.51 (s, 1H), 12.70 (br.s, 1H).

Example 162
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3 from Example 79 Starting from 120 mg (0.16 mmol) of ethyl 1,4-tetrahydropyrimidine-5-carboxylate, 83 mg (74% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.89 min; m / z = 479 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.89 (s, 3H), 5.18 (s, 2H), 7.42-7.47 (m, 1H), 7. 51-7.57 (m, 1H), 7.61-7.65 (m, 1H), 7.71 (d, 1H), 7.79-7.83 (m, 1H), 7.86- 7.89 (m, 1H), 8.33 (s, 1H), 8.51 (s, 1H), 12.70 (br.s, 1H).

Example 163
1- (2-carbamoyl-1-methyl-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3 4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was prepared and purified in the same manner as in Example 121 at 60 ° C. with a reaction time of 3.5 hours. 1- (2-carbamoyl-1-methyl-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1 from Example 81 After further purification by preparative HPLC (Method 9) starting from 116 mg (0.21 mmol) of ethyl 2,2,3,4-tetrahydropyrimidine-5-carboxylate, 40 mg (36% of theory) of the title compound were obtained. Obtained.

LC-MS (Method 1): Rt = 0.96 min; m / z = 502 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.47 (s, partially hidden by the DMSO signal), 4.16 (s, 3H), 5.13 (s, 2H), 7.34-7.40 (m, 1H), 7.42-7.47 (m, 1H), 7.54-7.58 (m, 1H), 7.59-7.64 ( m, 1H), 7.83 (d, 1H), 7.90-7.94 (m, 1H), 7.96-7.99 (m, 1H), 8.30-8.35 (m, 1H), 8.53 (s, 1H), 12.73 (br.s, 1H).

Example 164
1- (1-Ethyl-2-methyl-1H-benzimidazol-5-yl) -3- [3-fluoro-2- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3 4-tetrahydropyrimidine-5-carboxylic acid

  First, 1- (1-ethyl-2-methyl-1H-benzimidazol-5-yl) -3- [3-fluoro-2- (trifluoromethyl) benzyl] -2,4- from Example 83. 153 mg (0.30 mmol) of ethyl dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate was placed in 2.1 mL of glacial acetic acid and 1.1 mL of concentrated hydrochloric acid and stirred at 120 ° C. for 1 hour. The mixture was then cooled to room temperature and mixed with water and extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. To remove residual acetic acid, the residue was stirred with methanol / dichloromethane, concentrated again and dried in vacuo. This gave 120 mg (81% of theory) of the title compound.

LC-MS (Method 3): Rt = 1.02 min; m / z = 491 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.36 (t, 3H), 2.72 (s, 3H), 4.38 (q, 2H), 5.23 (s, 2H), 7.23-7.28 (m, 1H), 7.38-7.45 (m, 1H), 7.51-7.57 (m, 1H), 7.64-7.71 ( m, 1H), 7.86-7.93 (m, 2H), 8.54 (s, 1H), 12.71 (br.s, 1H).

Example 165
1- (1-Ethyl-1H-benzimidazol-5-yl) -3- [3-fluoro-2- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 1- (1-Ethyl-1H-benzimidazol-5-yl) -3- [3-fluoro-2- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3 from Example 90 Starting from 73 mg (0.15 mmol) of ethyl 1,4-tetrahydropyrimidine-5-carboxylate, 16 mg (23% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.89 min; m / z = 477 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.43 (t, 3H), 4.33 (q, 2H), 5.23 (s, 2H), 7.21-7. 27 (m, 1H), 7.37-7.45 (m, 2H), 7.63-7.71 (m, 1H), 7.76 (d, 1H), 7.84-7.88 ( m, 1H), 8.40 (s, 1H), 8.49 (s, 1H), 12.70 (br.s, 1H).

Example 166
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-ethyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-carboxylic acid

  First, 3- [2-chloro-3- (trifluoromethyl) benzyl] -1- (1-ethyl-1H-benzimidazol-5-yl) -2,4-dioxo-1, from Example 91, 53 mg (0.10 mmol) of ethyl 2,3,4-tetrahydropyrimidine-5-carboxylate was placed in 0.7 mL of glacial acetic acid and 0.4 mL of concentrated hydrochloric acid, and stirred at 120 ° C. for 1 hour. The mixture was then cooled to room temperature and mixed with water and extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 8). This gave 37 mg (75% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.94 min; m / z = 493 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.43 (t, 3H), 4.33 (q, 2H), 5.18 (s, 2H), 7.40-7. 45 (m, 1H), 7.51-7.57 (m, 1H), 7.60-7.64 (m, 1H), 7.76 (d, 1H), 7.79-7.83 ( m, 1H), 7.86-7.88 (m, 1H), 8.40 (s, 1H), 8.48 (s, 1H).

Example 167
1- (1-Ethyl-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-carboxylic acid

  In the same manner as in Example 166, the title compound was produced and purified. 1- (1-Ethyl-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3 from Example 80 Starting from 38 mg (0.08 mmol) of ethyl 1,4-tetrahydropyrimidine-5-carboxylate, 9 mg (25% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.94 min; m / z = 473 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.43 (t, 3H), 2.47 (s, 3H), 4.33 (q, 2H), 5.12 (s, 2H), 7.33-7.39 (m, 1H), 7.40-7.45 (m, 2H), 7.59-7.63 (m, 1H), 7.76 (d, 1H) 7.86-7.88 (m, 1H), 8.40 (s, 1H), 8.46 (s, 1H).

Example 168
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-ethyl-2-methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3 4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 166, the title compound was produced and purified. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-ethyl-2-methyl-1H-benzimidazol-5-yl) -2,4-dioxo-1 from Example 84 Starting from 114 mg (0.21 mmol) of ethyl 2,2,3,4-tetrahydropyrimidine-5-carboxylate, 93 mg (83% of theory) of the title compound were obtained.

LC-MS (Method 3): Rt = 1.09 min; m / z = 507 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.34 (t, 3H), 2.66 (s, 3H), 4.33 (q, 2H), 5.18 (s, 2H), 7.43-7.49 (m, 1H), 7.51-7.57 (m, 1H), 7.61-7.65 (m, 1H), 7.76-7.85 ( m, 3H), 8.51 (s, 1H), 12.70 (br.s, 1H).

Example 169
1- (1-cyclohexyl-2-methyl-1H-benzimidazol-5-yl) -3- [3-fluoro-2- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3 4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 166, the title compound was produced and purified. 1- (1-cyclohexyl-2-methyl-1H-benzimidazol-5-yl) -3- [3-fluoro-2- (trifluoromethyl) benzyl] -2,4-dioxo-1 from Example 85 Starting from 90 mg (0.15 mmol) of ethyl 2,2,3,4-tetrahydropyrimidine-5-carboxylate, 74 mg (81% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.01 min; m / z = 545 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.38-1.57 (m, 3H), 1.67-1.74 (m, 1H), 1.84-1.94 (M, 4H), 2.12-2.25 (m, 2H), 2.68 (s, 3H), 4.33-4.43 (m, 1H), 5.23 (s, 2H), 7.25 (d, 1H), 7.36-7.46 (m, 2H), 7.64-7.71 (m, 1H), 7.77-7.82 (m, 1H), 7. 92-8.01 (m, 1H), 8.51 (s, 1H), 12.70 (br.s, 1H).

Example 170
1- (1-Isopropyl-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-carboxylic acid

  First, 1- (1-Isopropyl-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1, from Example 93, 91 mg (0.18 mmol) of ethyl 2,3,4-tetrahydropyrimidine-5-carboxylate was added to 1.3 mL of glacial acetic acid and 0.6 mL of concentrated hydrochloric acid, and stirred at 120 ° C. for 1 hour. The mixture was then cooled to room temperature and mixed with water and extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was stirred with methanol and the solid was filtered and dried in vacuo. The filtrate was concentrated again and the residue was dried in vacuo. This gave a total of 61 mg (70% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.01 min; m / z = 487 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.56 (d, 6H), 2.47 (s, 3H), 4.78-4.87 (m, 1H), 5. 12 (s, 2H), 7.33-7.39 (m, 1H), 7.40-7.46 (m, 2H), 7.59-7.63 (m, 1H), 7.80 ( d, 1H), 7.87-7.90 (m, 1H), 8.48-8.52 (m, 2H), 12.71 (br.s, 1H).

Example 171
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-isopropyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-carboxylic acid

  First, 3- [2-chloro-3- (trifluoromethyl) benzyl] -1- (1-isopropyl-1H-benzimidazol-5-yl) -2,4-dioxo-1, from Example 86, 65 mg (0.12 mmol) of ethyl 2,3,4-tetrahydropyrimidine-5-carboxylate was placed in 0.9 mL of glacial acetic acid and 0.4 mL of concentrated hydrochloric acid and stirred at 120 ° C. for 1 hour. The mixture was then cooled to room temperature and mixed with water and extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was stirred with methanol and the solid was filtered, washed with methanol and dried in vacuo. The filtrate was concentrated and the residue was dried in vacuo. This gave a total of 44 mg (71% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.01 min; m / z = 507 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.55 (s, 3H), 1.57 (s, 3H), 4.78-4.87 (m, 1H), 5. 18 (s, 2H), 7.39-7.45 (m, 1H), 7.51-7.57 (m, 1H), 7.61-7.66 (m, 1H), 7.78- 7.83 (m, 2H), 7.86-7.89 (m, 1H), 8.50 (s, 1H), 8.52 (s, 1H), 12.70 (br.s, 1H) .

Example 172
3- (2,3-Dichlorobenzyl) -1- (1-isopropyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 171, the title compound was produced and purified. 3- (2,3-Dichlorobenzyl) -1- (1-isopropyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine from Example 87 Starting from 83 mg (0.17 mmol) of ethyl 5-carboxylate, 59 mg (72% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.99 min; m / z = 473 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.56 (d, 6H), 4.78-4.86 (m, 1H), 5.14 (s, 2H), 7. 26-7.30 (m, 1H), 7.32-7.38 (m, 1H), 7.40-7.44 (m, 1H), 7.57-7.61 (m, 1H), 7.80 (d, 1H), 7.86-7.89 (m, 1H), 8.48-8.52 (m, 2H), 12.70 (br.s, 1H).

Example 173
3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- [1- (cyclopropylmethyl) -1H-benzimidazol-5-yl] -2,4-dioxo-1,2,3 4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 171, the title compound was produced and purified. 3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- [1- (cyclopropylmethyl) -1H-benzimidazol-5-yl] -2,4-dioxo-1 from Example 92 Starting from 135 mg (0.24 mmol) of ethyl 2,2,3,4-tetrahydropyrimidine-5-carboxylate, 59 mg (45% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.00 min; m / z = 519 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.41-0.48 (m, 2H), 0.52-0.58 (m, 2H), 1.27-1.36 (M, 1H), 4.17 (d, 2H), 5.25 (s, 2H), 7.36-7.44 (m, 2H), 7.58-7.68 (m, 2H), 7.81 (d, 1H), 7.85-7.89 (m, 1H), 8.43 (s, 1H), 8.53 (s, 1H), 12.70 (br.s, 1H) .

Example 174
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-cyclobutyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-carboxylic acid

  In the same manner as in Example 171, the title compound was produced and purified. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-cyclobutyl-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3 from Example 88 Starting from 153 mg (0.25 mmol) of ethyl 1,4-tetrahydropyrimidine-5-carboxylate, 90 mg (68% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.02 min; m / z = 519 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.86-1.96 (m, 2H), 2.5-2.6 (m, partially hidden by the DMSO signal ) 4.99-5.09 (m, 1H), 5.18 (s, 2H), 7.40-7.45 (m, 1H), 7.50-7.57 (m, 1H), 7.60-7.66 (m, 1H), 7.75 (d, 1H), 7.79-7.83 (m, 1H), 7.87-7.90 (m, 1H), 8. 51 (s, 1H), 8.55 (s, 1H), 12.71 (br.s, 1H).

Example 175
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-1H-indazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-1H-indazol-5-yl) -2,4-dioxo-1,2,3 from Example 89 Starting from 228 mg (0.45 mmol) of ethyl 4-tetrahydropyrimidine-5-carboxylate, 170 mg (77% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.04 min; m / z = 479 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 4.10 (s, 3H), 5.18 (s, 2H), 7.51-7.57 (m, 2H), 7. 61-7.66 (m, 1H), 7.76-7.83 (m, 2H), 7.96-7.99 (m, 1H), 8.18 (s, 1H), 8.54 ( s, 1H), 12.71 (br.s, 1H).

Example 176
1- (1-Methyl-1H-indazol-5-yl) -2,4-dioxo-3-[(1R) -4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl ] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (R enantiomer)

  The title compound was prepared and purified in the same manner as in Example 121 with a reaction time of 45 minutes. 1- (1-Methyl-1H-indazol-5-yl) -2,4-dioxo-3- [4- (trifluoromethyl) -2,3-dihydro-1H-indene-1- from Example 76 Starting from 119 mg (0.24 mmol) of ethyl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate to give 81 mg (71% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.08 min; m / z = 471 (M + H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 2.45-2.54 (m, 1H), 2.65-2.72 (m, 1H), 3.13-3.24 (m 1H), 3.48-3.61 (m, 1H), 4.12 (s, 3H), 6.62-6.71 (m, 1H), 7.28-7.35 (m, 3H) ), 7.48-7.56 (m, 2H), 7.70 (s, 1H), 8.06 (s, 1H), 8.63 (s, 1H), 12.53 (s, 1H) .

Example 177
1- (1,3-Dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl ] -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 1- (1,3-Dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl) -3- [2-methyl-3- (from Example 94 Trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate starting from 195 mg (0.35 mmol) 153 mg (79% of theory) of the title compound Got.

LC-MS (Method 1): Rt = 1.11 min; m / z = 525 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.47 (s, 3H), 3.26 (s, 3H), 3.30 (s, partially hidden by water signal 5.10 (s, 2H), 7.13-7.17 (m, 1H), 7.20-7.24 (m, 1H), 7.26-7.30 (m, 1H) 7.32-7.42 (m, 2H), 7.59-7.63 (m, 1H), 8.48 (s, 1H), 12.74 (br.s, 1H).

Example 178
3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- (1,3-dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl ) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [3-Chloro-2- (trifluoromethyl) benzyl] -1- (1,3-dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzoate from Example 95 Starting from 120 mg (0.21 mmol) ethyl thiadiazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 98 mg (85% of theory) of the title compound Got.

LC-MS (Method 1): Rt = 1.11 min; m / z = 545 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.27 (s, partially hidden by DMSO signal), 3.30 (s, 3H), 5.23 (s, 2H), 7.13-7.18 (m, 1H), 7.18-7.23 (m, 1H), 7.24-7.27 (m, 1H), 7.31-7.36 ( m, 1H), 7.56-7.67 (m, 2H), 8.50 (s, 1H), 12.73 (br.s, 1H).

Example 179
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1,3-dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl ) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1,3-dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzoate from Example 96 Starting from 167 mg (0.29 mmol) of ethyl thiadiazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 129 mg (80% of theory) of the title compound Got.

LC-MS (Method 1): Rt = 1.12 min; m / z = 545 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.27 (s, 3H), 3.30 (s, 3H), 5.17 (s, 2H), 7.13-7. 18 (m, 1H), 7.20-7.24 (m, 1H), 7.25-7.28 (m, 1H), 7.50-7.56 (m, 1H), 7.56- 7.61 (m, 1H), 7.79-7.83 (m, 1H), 8.49 (s, 1H), 12.74 (br.s, 1H).

Example 180
1- (1,3-Dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl) -2,4-dioxo-3-[(1R) -4- (Trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (R enantiomer)

  The title compound was prepared and purified as in Example 121. 1- (1,3-Dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl) -2,4-dioxo-3- [4 from Example 97 Starting from 130 mg (0.23 mmol) of ethyl-(trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate After further purification by preparative HPLC (Method 8), 50 mg (40% of theory) of the title compound were obtained.

LC-MS (Method 4): Rt = 2.44 min; m / z = 537 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 2.32-2.44 (m, 1H), 2.51-2.63 (m, 1H), 3.04-3.16 (M, 1H), 3.20 (s, 3H), 3.23 (s, 3H), 3.36-3.47 (m, 1H), 6.51-6.60 (m, 1H), 6.65 (s, 1H), 6.75 (d, 1H), 6.89 (d, 1H), 7.21-7.30 (m, 2H), 7.42-7.49 (m, 1H), 8.44 (s, 1H).

Example 181
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2 from Example 16 Starting from 20 mg (0.04 mmol) of ethyl 1,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 14 mg (71% of theory) of the title compound were obtained.

LC-MS (Method 3): Rt = 1.16 min; m / z = 495 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.30 (s, 3H), 5.16 (s, 2H), 7.17-7.23 (m, 3H), 7. 49-7.55 (m, 1H), 7.60-7.64 (m, 1H), 7.78-7.83 (m, 1H), 8.44 (s, 1H), 11.14 ( s, 1H), 12.69 (br.s, 1H).

Example 182
1- (1-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 1- (1-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) -benzyl]-from Example 14 Starting from 129 mg (0.26 mmol) of ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 113 mg (93% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.94 min; m / z = 475 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.46 (s, 3H), 3.32 (s, 3H), 5.10 (s, 2H), 7.17-7. 23 (m, 3H), 7.32-7.38 (m, 1H), 7.40-7.45 (m, 1H), 7.58-7.63 (m, 1H), 8.43 ( s, 1H), 11.14 (s, 1H), 12.70 (br.s, 1H).

Example 183
3- (2,3-Dichlorobenzyl) -1- (1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3 4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- (2,3-Dichlorobenzyl) -1- (1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1 from Example 15 Starting from 30 mg (0.06 mmol) of ethyl 2,2,3,4-tetrahydropyrimidine-5-carboxylate, 22 mg (73% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.91 min; m / z = 461 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.30 (s, partially hidden by water signal), 5.12 (s, 2H), 7.20 (s, 3H), 7.25-7.29 (m, 1H), 7.30-7.36 (m, 1H), 7.56-7.61 (m, 1H), 8.43 (s, 1H) 11.14 (s, 1H), 12.69 (br.s, 1H).

Example 184
1- (6-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was prepared and purified as in Example 1. 1- (6-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5 from Example 27A -Starting from 200 mg (0.60 mmol) of ethyl carboxylate and 168 mg (0.66 mmol) of 1- (bromomethyl) -2-methyl-3- (trifluoromethyl) benzene, the title compound after further recrystallization from ethanol 207 mg (62% of theory) were obtained.

LC-MS (Method 1): Rt = 0.98 min; m / z = 503 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 2.09 (s, 3H), 2.45 (s, 3H), 4.18 (q, 2H), 5.08 (d, 2H), 6.89 (s, 1H), 7.12 (s, 1H), 7.30-7.36 (m, 2H), 7.57-7.62. (M, 1H), 8.37 (s, 1H), 10.80 (s, 1H).

Example 185
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  The title compound was produced in the same manner as in Example 37. 1- (6-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5 from Example 27A -After purification by preparative HPLC (Method 8) starting from 200 mg (0.60 mmol) of ethyl carboxylate and 182 mg (0.66 mmol) of 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene 178 mg (56% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.01 min; m / z = 523 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (t, 3H), 2.10 (s, 3H), 4.19 (q, 2H), 5.15 (s, 2H), 6.89 (s, 1H), 7.11 (s, 1H), 7.49-7.57 (m, 2H), 7.77-7.83 (m, 1H), 8.39. (S, 1H), 10.80 (s, 2H).

Example 186
3- [2-Chloro-3- (trifluoromethyl) benzyl] -2,4-dioxo-1- (2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -1,2, 3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was produced and purified in the same manner as in Example 121, with the reaction time being 1 hour. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -2,4-dioxo-1- (2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) from Example 37 Starting from 99 mg (0.19 mmol) of ethyl -1,2,3,4-tetrahydropyrimidine-5-carboxylate, 79 mg (85% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.89 min; m / z = 481 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 5.16 (s, 2H), 7.00-7.04 (m, 1H), 7.07-7.11 (m, 1H ), 7.13-7.16 (m, 1H), 7.49-7.55 (m, 1H), 7.59-7.64 (m, 1H), 7.78-7.83 (m) 1H), 8.43 (s, 1H), 10.87-10.92 (m, 2H), 12.68 (br.s, 1H).

Example 187
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was produced and purified in the same manner as in Example 121, with the reaction time being 1 hour. 1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] from Example 40 Starting from 280 mg (0.55 mmol) of ethyl -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 186 mg (69% of theory) of the title compound were obtained.

LC-MS (Method 5): Rt = 1.06 min; m / z = 476 (M + H) ^<+> .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.47 (s, 3H), 3.38 (s, 3H), 5.10 (s, 2H), 7.32-7. 47 (m, 4H), 7.58-7.66 (m, 2H), 8.47 (s, 1H), 12.74 (br.s, 1H).

Example 188
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was produced and purified in the same manner as in Example 121, with the reaction time being 1 hour. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) from Example 41 Starting from 250 mg (0.47 mmol) of ethyl -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 220 mg (91% of theory) of the title compound were obtained.

LC-MS (Method 5): Rt = 1.07 min; m / z = 496 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.38 (s, 3H), 5.16 (s, 2H), 7.38-7.47 (m, 2H), 7. 50-7.56 (m, 1H), 7.58-7.64 (m, 2H), 7.78-7.83 (m, 1H), 8.48 (s, 1H), 12.74 ( br.s, 1H).

Example 189
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-3-[(1R) -4- (trifluoromethyl)- 2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (R enantiomer)

  3.40 g (6.60 mmol) of the compound from Example 42 in 44 mL of glacial acetic acid and 22 mL of concentrated hydrochloric acid was stirred for 1 hour at reflux temperature. After some cooling (about 60 ° C.), the mixture was fully concentrated under reduced pressure. The amorphous residue was mixed with 50 mL of isopropanol and heated to reflux for 15 minutes, whereupon a solid formed. The suspension was cooled to 10 ° C. and the solid was then filtered off with suction. The solid was washed twice with isopropanol, 15 mL each time, filtered off with suction and dried under HV. This gave 2.53 g (79% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.12 min; m / z = 488 (M + H) ⁺ .

Chiral analytical HPLC (Method 14): Rt = 13.3 min; approx. 99% ee
¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 2.40-2.52 (m, 1H), 2.59-2.72 (m, 1H), 3.12-3.25 (M, 1H), 3.41 (s, 3H), 3.44-3.56 (m, 1H), 6.58-6.69 (m, 1H), 7.04-7.11 (m 1H), 7.15-7.21 (m, 1H), 7.24 (br.s, 1H), 7.29-7.38 (m, 2H), 7.53 (s, 1H), 8.54 (s, 1H), 12.39 (br.s, 1H).

Specific rotation α _D ²⁰ = + 135.3 ° (methanol, c = 0.43).

In a similar experiment, the specific rotation of the product was measured in. Chloroform: α _D ²⁰ = + 159.5 ° (chloroform, c = 0.395).

  X-ray structural analysis in complex with chymase confirmed the R configuration in this enantiomer.

Example 190
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-3-[(1S) -4- (trifluoromethyl)- 2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (S enantiomer)

  420 mg (0.80 mmol) of the compound from Example 43 in 7.7 mL of glacial acetic acid / concentrated hydrochloric acid 2: 1 (volume ratio) was heated to reflux for 1 hour. The reaction mixture was then concentrated on a rotary evaporator and the residue was dried under HV. This gave 390 mg (96% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.09 min; m / z = 488 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 2.37-2.53 (m, 1H), 2.66 (dtd, 1H), 3.10-3.26 (m, 1H ), 3.41 (s, 3H), 3.44-3.55 (m, 1H), 6.58-6.71 (m, 1H), 7.08 (d, 1H), 7.19 ( br.d, 1H), 7.24 (br.s, 1H), 7.30-7.38 (m, 2H), 7.50-7.59 (m, 1H), 8.55 (s, 1H).

  Chiral analytical HPLC (Method 14): Rt = 9.97 min, ca. 95% ee.

Specific rotation: α _D ²⁰ = -122.5 ° (c = 0.5, methanol).

Example 191
3- (2,3-dichlorobenzyl) -1- (3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2, 3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- (2,3-Dichlorobenzyl) -1- (3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo from Example 45 Starting from 210 mg (0.42 mmol) of ethyl -1,2,3,4-tetrahydropyrimidine-5-carboxylate, 180 mg (89% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.08 min; m / z = 476 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.28 (t, 3H), 3.90 (q, 2H), 5.12 (s, 2H), 7.23-7. 28 (m, 1H), 7.31-7.36 (m, 1H), 7.47 (s, 2H), 7.57-7.61 (m, 1H), 7.62-7.65 ( m, 1H), 8.48 (s, 1H), 12.70 (br.s, 1H).

Example 192
1- (3-Ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 1- (3-Ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] from Example 44 Starting from 185 mg (0.36 mmol) of ethyl -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 159 mg (90% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.10 min; m / z = 490 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.28 (t, 3H), 2.47 (s, 3H), 3.90 (q, 2H), 5.10 (s, 2H), 7.32-7.38 (m, 1H), 7.39-7.50 (m, 3H), 7.59-7.63 (m, 1H), 7.64-7.66 ( m, 1H), 8.48 (s, 1H), 12.72 (br.s, 1H).

Example 193
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (3-ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) from Example 46 Starting from 200 mg (0.37 mmol) of ethyl -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 165 mg (85% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.10 min; m / z = 510 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.28 (d, 3H), 3.90 (q, 2H), 5.17 (s, 2H), 7.42-7. 56 (m, 3H), 7.58-7.65 (m, 2H), 7.78-7.83 (m, 1H), 8.49 (s, 1H), 12.73 (br.s, 1H).

Example 194
1- (3-Ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -3- [3-fluoro-2- (trifluoromethyl) benzyl] -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 1- (3-Ethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -3- [3-fluoro-2- (trifluoromethyl) benzyl] from Example 47 Starting from 150 mg (0.29 mmol) of ethyl -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 105 mg (73% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.05 min; m / z = 494 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.28 (t, 3H), 3.90 (q, 2H), 5.21 (s, 2H), 7.19-7. 25 (m, 1H), 7.38-7.51 (m, 3H), 7.61-7.70 (m, 2H), 8.50 (s, 1H), 12.72 (br.s, 1H).

Example 195
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -3- [2-methyl-3- (trifluoromethyl) -benzyl from Example 48 Starting from 390 mg (0.75 mmol) of ethyl 2,2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 314 mg (81% of theory) of the title compound were obtained.

LC-MS (Method 3): Rt = 1.33 min; m / z = 492 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.47 (s, 3H), 3.45 (s, 3H), 5.10 (s, 2H), 7.32-7. 38 (m, 1H), 7.39-7.43 (m, 1H), 7.46 (d, 1H), 7.60 (s, 2H), 7.89 (d, 1H), 8.52 (S, 1H), 12.73 (br.s, 1H).

Example 196
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) from Example 49 Starting from 216 mg (0.40 mmol) of ethyl -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 155 mg (72% of theory) of the title compound were obtained.

LC-MS (Method 3): Rt = 1.33 min; m / z = 512 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.45 (s, 3H), 5.17 (s, 2H), 7.46 (d, 1H), 7.49-7. 64 (m, 3H), 7.78-7.84 (m, 1H), 7.89 (d, 1H), 8.53 (s, 1H), 12.73 (br.s, 1H).

Example 197
3- [3-Fluoro-2- (trifluoromethyl) benzyl] -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [3-Fluoro-2- (trifluoromethyl) benzyl] -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) from Example 50 Starting from 241 mg (0.46 mmol) of ethyl -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 180 mg (73% of theory) of the title compound were obtained.

LC-MS (Method 3): Rt = 1.27 min; m / z = 496 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.45 (s, 3H), 5.21 (s, 2H), 7.19-7.25 (m, 1H), 7. 37-7.49 (m, 2H), 7.55-7.60 (m, 1H), 7.62-7.70 (m, 1H), 7.86-7.90 (m, 1H), 8.53 (s, 1H), 12.73 (br.s, 1H).

Example 198
1- (1,3-Benzothiazol-6-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5 -Carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 1- (1,3-Benzothiazol-6-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4 from Example 98 Starting from 204 mg (0.41 mmol) of ethyl tetrahydropyrimidine-5-carboxylate, 160 mg (82% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.07 min; m / z = 462 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.47 (partially hidden by the DMSO signal), 5.12 (s, 2H), 7.33-7.39 ( m, 1H), 7.42-7.47 (m, 1H), 7.58-7.64 (m, 1H), 7.70-7.75 (m, 1H), 8.22 (d, 1H), 8.39-8.43 (m, 1H), 8.61 (s, 1H), 9.54 (s, 1H), 12.75 (br.s, 1H).

Example 199
1- [3-Hydroxy-1-methyl-2-oxo-3- (trifluoromethyl) -2,3-dihydro-1H-indol-5-yl] -3- [2-methyl-3- (trifluoro Methyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemic)

  The title compound was produced and purified in the same manner as in Example 121 with a reaction time of 20 minutes. 1- [3-Hydroxy-1-methyl-2-oxo-3- (trifluoromethyl) -2,3-dihydro-1H-indol-5-yl] -3- [2-methyl- from Example 63 Starting from 74 mg (0.12 mmol) of ethyl 3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 37 mg (theoretical amount) 53%).

LC-MS (Method 5): Rt = 1.09 min; m / z = 558 (M + H) ^<+> .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.46 (s, 3H), 3.22 (s, 3H), 5.10 (s, 2H), 7.29 (d, 1H), 7.32-7.38 (m, 1H), 7.41-7.45 (m, 1H), 7.58-7.63 (m, 1H), 7.66-7.73 ( m, 2H), 7.92 (s, 1H), 8.44 (s, 1H), 12.74 (br.s, 1H).

Example 200
1- [3-Fluoro-1-methyl-2-oxo-3- (trifluoromethyl) -2,3-dihydro-1H-indol-5-yl] -3- [2-methyl-3- (trifluoro Methyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemic)

  In the same manner as in Example 121, the title compound was produced and purified. 1- [3-Fluoro-1-methyl-2-oxo-3- (trifluoromethyl) -2,3-dihydro-1H-indol-5-yl] -3- [2-methyl- from Example 64 Starting from 85 mg (0.14 mmol) of ethyl 3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 66 mg (theoretical amount of 82%).

LC-MS (Method 1): Rt = 1.18 min; m / z = 560 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.46 (s, partially hidden by DMSO signal), 3.26 (s, partially hidden by water signal 5.10 (s, 2H), 7.31-7.38 (m, 1H), 7.39-7.45 (m, 2H), 7.60 (d, 1H), 7.82 -7.88 (m, 1H), 7.95 (s, 1H), 8.57 (s, 1H), 12.75 (br.s, 1H).

Example 201
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (3-hydroxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2 , 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemate)

The title compound was produced and purified in the same manner as in Example 121 with the reaction time being 45 minutes. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (3-hydroxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indole-5 from Example 62 Starting from 124 mg (0.22 mmol) of ethyl -yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 54 mg (50% of theory) of the title compound were obtained. Example 202 was 24 mg (22% of theory). Analytical data for the title compound:
LC-MS (Method 1): Rt = 0.95 min; m / z = 524 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.41 (s, 3H), 3.14 (s, 3H), 5.16 (s, 2H), 6.12 (s, 1H), 7.14 (d, 1H), 7.47-7.57 (m, 3H), 7.59-7.64 (m, 1H), 7.78-7.83 (m, 1H) , 8.42 (s, 1H), 12.73 (br.s, 1H).

Example 202
1- (3-Chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -3- [2-chloro-3- (trifluoromethyl) benzyl] -2 , 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound (24 mg) was isolated by the synthesis of Example 201.

LC-MS (Method 1): Rt = 1.09 min; m / z = 542 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.87 (s, 3H), 3.22 (s, 3H), 5.17 (s, 2H), 7.26 (d, 1H), 7.51-7.56 (m, 1H), 7.57-7.64 (m, 2H), 7.77-7.84 (m, 2H), 8.48 (s, 1H) 12.75 (br.s, 1H).

Example 203
3- [2-Methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1- (2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -1,2, 3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was prepared and purified in the same manner as in Example 121 with a reaction time of 15 minutes. 1- (1-Methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl) -3- [2-methyl-3- (trifluoromethyl) from Example 100 Starting from 265 mg (0.51 mmol) of ethyl [benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, after purification by preparative HPLC (Method 8) 121 mg of the title compound (46% of theory) was obtained.

LC-MS (Method 1): Rt = 1.03 min; m / z = 490 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.47 (s, 3H), 3.3 (hidden by water signal), 5.10 (s, 2H), 5. 30 (s, 2H), 7.21-7.26 (m, 1H), 7.31-7.43 (m, 2H), 7.45-7.48 (m, 1H), 7.53- 7.62 (m, 2H), 8.46 (s, 1H), 12.72 (br.s, 1H).

Example 204
1- (1-Methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl) -2,4-dioxo-3-[(1R) -4- (trifluoromethyl ) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (R enantiomer)

  The title compound was prepared and purified in the same manner as in Example 121 with a reaction time of 45 minutes. 1- (1-Methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl) -2,4-dioxo-3- [4- (trifluoro from Example 101 Starting from 135 mg (0.25 mmol) of methyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate 81 mg (theory) 59% of the amount).

LC-MS (Method 1): Rt = 1.04 min; m / z = 502 (M + H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 2.39-2.52 (m, 1H), 2.64-2.71 (m, 1H), 3.12-3.25 (m 1H), 3.41 (s, 3H), 3.47-3.61 (m, 1H), 5.22 (s, 2H), 6.60-6.70 (m, 1H), 7. 05 (d, 1H), 7.15 (s, 1H), 7.28-7.36 (m, 3H), 7.50-7.57 (m, 1H), 8.53 (s, 1H) 12.18-12.70 (m, 2H).

Example 205
3- [2-Methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indole-6 Yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was produced and purified in the same manner as in Example 121 with the reaction time being 45 minutes. 3- [2-Methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H from Example 59 Starting from 127 mg (0.24 mmol) of ethyl-indol-6-yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylate, after further purification by preparative HPLC (Method 8), the title compound 76 mg (63% of theory) were obtained.

LC-MS (Method 1): Rt = 1.08 min; m / z = 502 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.30 (s, 6H), 2.47 (s, 3H), 3.14 (s, 3H), 5.11 (s, 2H), 7.19-7.24 (m, 1H), 7.25-7.28 (m, 1H), 7.32-7.43 (m, 2H), 7.51 (d, 1H) 7.61 (d, 1H), 8.48 (s, 1H), 12.74 (br.s, 1H).

Example 206
3- [2-Chloro-3- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indole-6 Yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was produced and purified in the same manner as in Example 121 except that cyclohexane was used in place of MTBE in the post-treatment, and the reaction time was 2 hours. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H from Example 60 Starting from 125 mg (0.35 mmol) of ethyl -indol-6-yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylate, 134 mg (65% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.08 min; m / z = 522 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.30 (s, 6H), 3.15 (s, 3H), 5.17 (s, 2H), 7.19-7. 24 (m, 1H), 7.24-7.27 (m, 1H), 7.48-7.56 (m, 2H), 7.58-7.62 (m, 1H), 7.78- 7.83 (m, 1H), 8.49 (s, 1H), 12.74 (br.s, 1H).

Example 207
3- [3-Chloro-2- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indole-6 Yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was produced and purified in the same manner as in Example 121 with the reaction time being 45 minutes. 3- [3-Chloro-2- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H from Example 61 Starting from 122 mg (0.22 mmol) of ethyl -indol-6-yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylate, 87 mg (71% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.12 min; m / z = 522 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.30 (s, 6H), 3.15 (s, 3H), 5.24 (br.s, 2H), 7.19- 7.23 (m, 1H), 7.23-7.26 (m, 1H), 7.33-7.37 (m, 1H), 7.51 (d, 1H), 7.57-7. 67 (m, 2H), 8.50 (s, 1H), 12.73 (br.s, 1H).

Example 208
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -2 , 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  First, 3- [2-chloro-3- (trifluoromethyl) benzyl] -1- (3,3-dimethyl-2-oxo-2,3-dihydro- from Example 68 in THF (5 mL). 1H-Indol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 371 mg (0.69 mmol) was placed under argon at 0 ° C., and 29 mg of sodium hydride was added. (Content 60%, 0.72 mmol) was added. The mixture was stirred at room temperature for 30 minutes and then cooled again to 0 ° C. A solution of 113 mg (0.72 mmol) iodoethane in THF (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 days. For workup, the mixture was mixed with water and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC (Method 7). This gave 50 mg (12% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.37 min; m / z = 564 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.16 (t, 3H), 1.24 (t, 3H), 1.30 (s, 6H), 3.70 (q, 2H), 4.20 (q, 2H), 5.16 (s, 2H), 7.21 (dd, 1H), 7.31 (d, 1H), 7.49-7.60 (m, 3H) ), 7.78-7.82 (m, 1H), 8.52 (s, 1H).

Example 209
1- (4-Methylquinolin-7-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carvone Hydrochloride

  In the same manner as in Example 121, the title compound was produced and purified. 1- (4-Methylquinolin-7-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydro from Example 99 Starting from 200 mg (0.40 mmol) of ethyl pyrimidine-5-carboxylate, 173 mg (91% of theory) of the title compound were obtained.

LC-MS (Method 3): Rt = 1.25 min; m / z = 470 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.48 (s, 3H), 2.80 (s, 3H), 3.80 (br.s, 1H), 5.14 ( s, 2H), 7.34-7.40 (m, 1H), 7.46-7.51 (m, 1H), 7.59-7.65 (m, 2H), 7.84-7. 90 (m, 1H), 8.28-8.36 (m, 2H), 8.68 (s, 1H), 8.93-8.98 (m, 1H), 12.75 (br.s, 1H).

Example 210
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (3,3-dimethyl-2,3-dihydro-1H-indol-6-yl) -2,4-dioxo-1,2 , 3,4-Tetrahydropyrimidine-5-carboxylic acid

  228 mg (0.40 mmol) of the compound from Example 69 in 4.4 mL of glacial acetic acid / concentrated hydrochloric acid 2: 1 (volume ratio) was stirred for 1 hour at 120 ° C. (bath temperature) After cooling to room temperature, the mixture Was combined with water and extracted three times with dichloromethane, the combined organic phases were dried over magnesium sulfate and concentrated on a rotary evaporator, the residue was stirred in MTBE, the solid formed was filtered and a small amount of MTBE was filtered. And dried under HV, which gave 160 mg (80% of theory) of the title compound.

LC-MS (Method 5): Rt = 1.23 min; m / z = 494 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.25 (s, 6H), 3.25 (s, 2H), 5.15 (s, 2H), 5.88 (br. s, 1H), 6.59 (s, 1H), 6.65 (d, 1H), 7.09 (d, 1H), 7.47-7.55 (m, 1H), 7.56-7 .61 (m, 1H), 7.80 (d, 1H), 8.36 (s, 1H), 12.67 (br.s, 1H).

Example 211
1- (1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl) -3- [2-chloro-3- (trifluoromethyl) benzyl] -2,4-dioxo -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  First, 160 mg (0.32 mmol) of the compound from Example 210 was placed in THF (1.4 mL), then 90 μL (0.65 mmol) of triethylamine and 34 μL (0.36 mmol) of acetic anhydride were added, and the mixture was allowed to come to room temperature. And stirred overnight. The reaction mixture was then mixed with 1M hydrochloric acid and extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was stirred with methanol and the solid was filtered and dried in vacuo. This gave 85 mg (47% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.13 min; m / z = 536 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.34 (s, 6H), 2.18 (s, 3H), 3.94 (s, 2H), 5.15 (s, 2H), 7.16-7.21 (m, 1H), 7.38-7.43 (m, 1H), 7.48-7.54 (m, 1H), 7.61-7.65 ( m, 1H), 7.77-7.82 (m, 1H), 8.13-8.16 (m, 1H), 8.42 (s, 1H), 12.69 (br.s, 1H) .

Example 212
1- (3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2 , 3,4-Tetrahydropyrimidine-5-carboxylic acid

  Analogously to Example 210, 253 mg (0.47 mmol) of the compound from Example 70 was hydrolyzed and the product was purified. This gave 174 mg (77% of theory) of the title compound.

LC-MS (Method 5): Rt = 1.23 min; m / z = 474 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (s, 6H), 2.46 (s, 3H), 3.24 (s, 2H), 5.09 (s, 2H), 5.86 (br.s, 1H), 6.58 (s, 1H), 6.64 (d, 1H), 7.08 (d, 1H), 7.26-7.45 (m) 2H), 7.60 (d, 1H), 8.35 (s, 1H), 12.68 (br.s, 1H).

Example 213
1- (1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 211, the title compound was produced and purified. 1- (3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4 from Example 212 Starting from 74 mg (0.36 mmol) of -dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid, 135 mg (70% of theory) of the title compound were obtained.

LC-MS (Method 5): Rt = 1.18 min; m / z = 516 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.34 (s, 6H), 2.18 (s, 3H), 2.46 (s, 3H), 3.93 (s, 2H), 5.09 (s, 2H), 7.16-7.21 (m, 1H), 7.31-7.37 (m, 1H), 7.38-7.44 (m, 1H) 7.57-7.62 (m, 1H), 8.12-8.15 (m, 1H), 8.40 (s, 1H), 12.69 (br.s, 1H).

Example 214
1- (1-Methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 1- (1-Methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2 from Example 102 Starting from 267 mg (0.51 mmol) of ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 218 mg (83% of theory) of the title compound were obtained.

LC-MS (Method 3): Rt = 1.28 min; m / z = 488 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.47 (s, 3H), 2.56-2.61 (m, 2H), 2.89-2.94 (m, 2H) ), 3.28 (s, 3H), 5.10 (s, 2H), 7.20-7.24 (m, 1H), 7.32-7.46 (m, 4H), 7.58- 7.62 (m, 1H), 8.43 (s, 1H), 12.72 (br.s, 1H).

Example 215
1- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2,4-dioxo-3-[(1R) -4- (trifluoromethyl) -2, 3-Dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (R enantiomer)

  The title compound was prepared and purified in the same manner as in Example 121 with a reaction time of 45 minutes. 1- (1-Methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -2,4-dioxo-3- [4- (trifluoromethyl) -2 from Example 103 , 3-Dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate starting from 83 mg (0.15 mmol) 39 mg (46% of theory) of the title compound )

LC-MS (Method 1): Rt = 1.10 min; m / z = 500 (M + H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 2.42−2.52 (m, 1H), 2.63-2.66 (m, 1H, partially hidden by DMSO signal ), 2.69 (t, 2H), 2.95 (t, 2H), 3.12-3.20 (m, 1H, 3.37 (s, 3H), 3.48-3.60 (m) 1H), 6.60-6.71 (m, 1H), 7.06 (d, 1H), 7.14 (s, 1H), 7.21 (d, 1H), 7.28-7. 34 (m, 2H), 7.50-7.56 (m, 1H), 8.55 (s, 1H), 12.49 (s, 1H).

Example 216
3- (2-Methyl-3-nitrobenzyl) -1- (4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  First, 1- (4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -2,4-dioxo-1,2,3 from Example 119A. 200 mg (0.58 mmol) of ethyl 1,4-tetrahydropyrimidine-5-carboxylate was placed in acetonitrile (7.5 mL). 108 mg (0.58 mmol) of 2-methyl-3-nitrobenzyl chloride, 160 mg (1.16 mmol) of potassium carbonate and 48 mg (0.29 mmol) of potassium iodide were added, and the mixture was stirred at 60 ° C. for 41 hours. The mixture cooled to room temperature was completely separated by preparative HPLC (Method 8) and the isolated product was dried under HV. This gave 218 mg (75% of theory) of the title compound.

LC-MS (Method 3): Rt = 1.13 min; m / z = 495 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 2.41 (s, 3H), 4.21 (q, 2H), 3.30 (s, 3H), 4.71 (s, 2H), 5.06 (s, 2H), 7.22-7.32 (m, 3H), 7.36 (t partially hidden by water signal 1H), 7.41 (d, 1H), 7.72 (d, 1H), 8.38 (s, 1H).

Example 217
1- (3-Isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3-[(1R) -4- (trifluoromethyl ) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (R enantiomer)

  122 mg (0.22 mmol) of the compound from Example 114 was heated in 3.8 mL of glacial acetic acid / concentrated hydrochloric acid 2: 1 (volume ratio) to 120 ° C. (bath temperature) for 1 hour. After cooling to room temperature, 30 mL of water was added and the precipitated product was filtered off with suction. The solid was washed with water and dried under HV. This gave 107 mg (91% of theory) of the title compound.

LC-MS (Method 3): Rt = 2.43 min; m / z = 529 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.42 (d, 3H), 1.43 (d, 3H), 2.34-2.46 (m, 1H), 2. 52-2.64 (m, 1H), 3.04-3.16 (m, 1H), 3.31 (s, 3H), 3.37-3.50 (m, 1H), 4.54 ( sept, 1H), 6.51-6.62 (m, 1H), 6.88-7.01 (m, 3H), 7.21-7.31 (m, 2H), 7.46 (d, 1H), 8.49 (s, 1H), 12.29 (br.s, 1H).

Example 218
3- [2-Chloro-3- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indole-5 Yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H from Example 52 Starting from 200 mg (0.36 mmol) of ethyl -indol-5-yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylate, 161 mg (83% of theory) of the title compound were obtained.

LC-MS (Method 3): Rt = 1.29 min; m / z = 522 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.30 (s, 6H), 3.18 (s, 3H), 5.17 (s, 2H), 7.15 (d, 1H), 7.43-7.48 (m, 1H), 7.50-7.56 (m, 2H), 7.57-7.62 (m, 1H), 7.78-7.83 ( m, 1H), 8.46 (s, 1H), 12.73 (br.s, 1H).

Example 219
3- [2-Methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indole-5 Yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [2-Methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H from Example 53 Starting from 200 mg (0.38 mmol) of ethyl -indol-5-yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylate, 153 mg (80% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.07 min; m / z = 502 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.29 (s, 6H), 2.47 (s, 3H), 3.17 (s, 3H), 5.11 (s, 2H), 7.15 (d, 1H), 7.32-7.42 (m, 2H), 7.46 (dd, 1H), 7.54 (d, 1H), 7.58-7.64. (M, 1H), 8.45 (s, 1H), 12.73 (br.s, 1H).

Example 220
3- [3-Chloro-2- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indole-5 Yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [3-Chloro-2- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H from Example 54 Starting from 109 mg (0.20 mmol) of ethyl -indol-5-yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylate, 83 mg (79% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.10 min; m / z = 522 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.29 (s, 6H), 3.17 (s, 3H), 5.24 (br.s, 2H), 7.15 ( d, 1H), 7.32-7.37 (m, 1H), 7.42-7.47 (m, 1H), 7.50-7.54 (m, 1H), 7.57-7. 67 (m, 2H), 8.47 (s, 1H), 12.71 (br.s, 1H).

Example 221
3- [3-Fluoro-2- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indole-5 Yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- [3-Fluoro-2- (trifluoromethyl) benzyl] -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H from Example 55 Starting from 230 mg (0.43 mmol) of ethyl -indol-5-yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylate, 193 mg (85% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.02 min; m / z = 506 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.29 (s, 6H), 3.17 (s, 3H), 5.22 (s, 2H), 7.15 (d, 1H), 7.18-7.24 (m, 1H), 7.38-7.43 (m, 1H), 7.43-7.47 (m, 1H), 7.52-7.54 ( m, 1H), 7.63-7.70 (m, 1H), 8.46 (s, 1H), 12.72 (br.s, 1H).

Example 222
3- (2,3-Dichlorobenzyl) -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -1,2 , 3,4-Tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 121, the title compound was produced and purified. 3- (2,3-Dichlorobenzyl) -2,4-dioxo-1- (1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl from Example 56 Starting from 200 mg (0.39 mmol) ethyl) -1,2,3,4-tetrahydropyrimidine-5-carboxylate, 173 mg (90% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.05 min; m / z = 488 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.29 (s, 6H), 3.17 (s, 3H), 5.13 (s, 2H), 7.15 (d, 1H), 7.22-7.27 (m, 1H), 7.34 (t, 1H), 7.45 (dd, 1H), 7.54 (d, 1H), 7.57-7.61 (M, 1H), 8.45 (s, 1H), 12.72 (br.s, 1H).

Example 223
2,4-Dioxo-3- [4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1- (1,3,3-trimethyl-2-oxo-2,3 -Dihydro-1H-indol-5-yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemic)

  In the same manner as in Example 131, the title compound was produced and purified. 2,4-Dioxo-3- [4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1- (1,3,3-trimethyl-2-2 from Example 57 By HPLC (Method 8) starting from 507 mg (0.93 mmol) of ethyl oxo-2,3-dihydro-1H-indol-5-yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylate After purification, 131 mg (26% of theory) of the title compound were obtained.

LC-MS (Method 5): Rt = 1.15 min; m / z = 514 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.29 (br.s, 6H), 2.38-2.47 (m, 1H), 2.46-2.48 (m 1H, hidden by DMSO signal), 3.03-3.14 (m, 1H), 3.17 (s, 3H), 3.20-3.27 (m, 1H, partly water Hidden by the signal), 6.34-6.60 (m, 1H), 7.08-7.18 (m, 1H), 7.33-7.46 (m, 2H), 7.47- 7.58 (m, 3H), 8.38 (s, 1H), 12.69 (br.s, 1H).

Example 224
2,4-Dioxo-3-[(1R) -4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1- (1,3,3-trimethyl-2-oxo -2,3-dihydro-1H-indol-5-yl) -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (R enantiomer)

  In the same manner as in Example 217, 147 mg (0.27 mmol) of the compound from Example 58 was hydrolyzed and the product was isolated. This gave 120 mg (84% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.14 min; m / z = 514 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.29 (br.s, 6H), 2.39-2.46 (m, 1H), 2.46-2.60 (m 1H, hidden by DMSO signal), 3.04-3.18 (m, 1H), 3.17 (s, 3H), 3.22-3.36 (m, 1H partially water signal 6.34-6.61 (br.m, 1H), 7.13 (d, 1H), 7.33-7.46 (m, 2H), 7.47-7.57. (M, 3H), 8.38 (s, 1H), 12.69 (br.s, 1H).

α _D ²⁰ [chloroform, c = 0.385] = + 130.1 °.

Example 225
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1′-methyl-2′-oxo-1 ′, 2′-dihydrospiro [cyclopropane-1,3′-indole]- 5'-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 131, the title compound was produced and purified. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1'-methyl-2'-oxo-1 ', 2'-dihydrospiro [cyclopropane-1,3 from Example 65 '-Indol] -5'-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate starting from 147 mg (0.26 mmol) by HPLC (Method 7) After purification, 30 mg (21% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.08 min; m / z = 520 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.5-1.60 (m, 2H), 1.65-1.70 (m, 2H), 3.26 (s, 3H ), 5.16 (s, 2H), 7.20-7.23 (m, 2H), 7.41-7.46 (m, 1H), 7.50-7.55 (m, 1H), 7.56-7.60 (m, 1H), 7.78-7.83 (m, 1H), 8.46 (s, 1H), 12.73 (br.s, 1H).

Example 226
1- (1′-methyl-2′-oxo-1 ′, 2′-dihydrospiro [cyclopropane-1,3′-indole] -5′-yl) -3- [2-methyl-3- (tri Fluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  In the same manner as in Example 131, the title compound was produced and purified. 1- (1′-Methyl-2′-oxo-1 ′, 2′-dihydrospiro [cyclopropane-1,3′-indole] -5′-yl) -3- [2-methyl from Example 66 By HPLC (Method 7) starting from 130 mg (0.24 mmol) of ethyl-3- (trifluoromethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate After purification, 27 mg (22% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 1.08 min; m / z = 500 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.5-1.60 (m, 2H), 1.65 to 1.69 (m, 2H), 2.46 (s, 3H ), 3.26 (s, 3H), 5.10 (s, 2H), 7.18-7.24 (m, 2H), 7.32-7.40 (m, 2H), 7.42- 7.46 (m, 1H), 7.59-7.63 (m, 1H), 8.45 (s, 1H), 12.73 (br.s, 1H).

Example 227
1- (1'-methyl-2'-oxo-1 ', 2'-dihydrospiro [cyclopropane-1,3'-indole] -5'-yl) -2,4-dioxo-3-[(1R ) -4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (R enantiomer)

  1- (1′-Methyl-2′-oxo-1 ′, 2′-dihydrospiro [cyclopropane-1,3] from Example 67 in 117 mL of acetic acid / water / concentrated sulfuric acid mixture (12: 8: 1). '-Indol] -5'-yl) -2,4-dioxo-3- [4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4 -Ethyl tetrahydropyrimidine-5-carboxylate (7.81 g, purity 92%, 13.31 mmol) was stirred at 120 ° C for 2.5 hours. The cooled reaction mixture was mixed with water and the precipitated solid was filtered off with suction, washed with water and dried under high vacuum. The mother liquor was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by HPLC (Method 7) with the previously isolated solid. The isolated product (purity 95%) was dissolved in boiling 2-propanol and the solution was cooled overnight. The solid formed was filtered off with suction, washed with 2-propanol and then dried under high vacuum. This gave 5.22 g (74% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.08 min; m / z = 512 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.46-1.53 (m, 2H), 1.62-1.69 (m, 2H), 2.31-2.44 (M, 1H), 2.50-2.63 (m, 1H), 3.04-3.14 (m, 1H), 3.20 (s, 3H), 3.35-3.48 (m 1H), 6.50-6.60 (m, 1H), 6.71 (br.s, 1H), 6.90 (d, 1H), 7.08-7.16 (m, 1H), 7.20-7.29 (m, 2H), 7.42-7.49 (m, 1H), 8.44 (s, 1H).

Example 228
3-[(3-Chloro-4-methyl-2-thienyl) methyl] -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2, 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  Glacial acetic acid / concentrated hydrochloric acid 2: 1 22 mg (43 μmol) of the compound from Example 105 in 1 mL was heated to 120 ° C. (bath temperature) for 4 hours. After cooling to room temperature, 10 mL of water was added and the precipitated product was filtered off with suction. The solid was stirred with diethyl ether, again filtered off with suction and dried under HV. This gave 15 mg (74% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.97 min; m / z = 461 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.12 (s, 3H), 3.33 (s, 3H), 3.37 (s, 3H), 5.21 (s, 2H), 7.20 (dd, 1H), 7.27 (d, 1H), 7.30 (s, 1H), 7.37 (d, 1H), 8.37 (s, 1H), 12. 74 (br.s, 1H).

Example 229
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-3-[(1R) -4- (trifluoromethyl)- 2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (R enantiomer)

  Glacial acetic acid / concentrated hydrochloric acid 2: 1 6.20 g (11.3 mmol) of the compound from Example 51 in 150 mL was heated to 120 ° C. (bath temperature) for 1 hour. After cooling to room temperature, the reaction mixture was poured into 1 liter of ice water. The precipitated product was filtered off with suction. The solid was stirred with diethyl ether, again filtered off with suction and dried under HV. This gave 5.04 g (88% of theory) of the title compound.

LC-MS (Method 5): Rt = 1.14 min; m / z = 504 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 2.39-2.53 (m, 1H), 2.60-2.72 (m, 1H), 3.12-3.24 (M, 1H), 3.42-3.56 (m, 4H), 6.58-6.71 (m, 1H), 7.15 (d, 1H), 7.26-7.38 (m 3H), 7.45 (s, 1H), 7.50-7.58 (m, 1H), 8.55 (s, 1H).

  The following additional data has been collected for yet another batch of title compound produced in the same manner.

α _D ²⁰ [chloroform, c = 0.365] = + 148.6 °.

Example 230
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- (5-methoxy-2,3-dihydro-1H-inden-1-yl) -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemate)

  Heat the compound 86 mg (0.18 mmol) from Example 120 and 49 mg (0.58 mmol) sodium bicarbonate in 2 mL acetonitrile and 2 mL water at reflux for 6 hours. After cooling to room temperature, the mixture was acidified by adding 1N hydrochloric acid and separated directly by preparative HPLC (Method 7). This gave 24 mg (29% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.90 min; m / z = 463 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.31-2.47 (m, 2H), 2.83-2.95 (m, 1H), 3.09-3.22 (M, 1H), 3.34 (s, 6H), 3.72 (s, 3H), 6.29-6.47 (m, 1H), 6.67-6.74 (m, 1H), 6.79 (s, 1H), 7.08 (d, 1H), 7.13-7.21 (m, 1H), 7.22-7.30 (m, 1H), 7.37 (s, 1H), 8.38 (s, 1H), 12.74 (br.s, 1H).

Example 231
3- (4,6-Difluoro-2,3-dihydro-1H-inden-1-yl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5 Yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemic)

  In the same manner as in Example 217, 173 mg (0.35 mmol) of the compound from Example 106 was hydrolyzed. This gave 130 mg (80% of theory) of the title compound.

LC-MS (Method 5): Rt = 0.99 min; m / z = 469 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.38-2.48 (m, 2H, partially hidden by DMSO signal), 2.84-2.98 (m 1H), 3.02-3.18 (m, 1H), 3.34 (br.s, 3H), 6.22-6.60 (m, 1H), 7.03 (t, 2H), 7.12-7.29 (m, 2H), 7.31-7.43 (m, 1H), 8.38 (s, 1H), 12.67 (br.s, 1H).

Example 232
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- (6-methyl-2,3-dihydro-1H-inden-1-yl) -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemate)

  First, 127 mg (0.27 mmol) of the compound from Example 107 was placed in 2.5 mL of acetonitrile. Sodium bicarbonate (74 mg, 0.88 mmol) and water (2.5 mL) were added, and the mixture was heated to reflux for 6 hours. After cooling to room temperature, the mixture was acidified with 1N hydrochloric acid and completely separated by preparative HPLC (Method 7). This gave 78 mg (65% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.98 min; m / z = 447 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.25 (s, 3H), 2.35-2.45 (m, 2H), 2.82-2.93 (m, 1H ), 3.04-3.18 (m, 1H), 3.31 (s, 3H), 3.36 (s, 3H), 6.23-6.54 (m, 1H), 6.96- 7.03 (m, 2H), 7.10 (d, 1H), 7.16-7.30 (m, 2H), 7.33-7.45 (m, 1H), 8.39 (s, 1H), 12.73 (br.s, 1H).

Example 233
3- (4-Methoxy-2,3-dihydro-1H-inden-1-yl) -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl (racemate)

  227 μL of diisopropyl azodicarboxylate in a solution of 200 mg (0.58 mmol) of the compound from Example 31A and 453 mg (1.73 mmol) of triphenylphosphine in THF / DMF 1: 1 (volume ratio) (15.8 mL) under argon. (1.15 mmol) was added dropwise. Then 123 mg (0.75 mmol) of the compound from Example 103A was added and the mixture was stirred at room temperature for 1 hour. While cooling with ice, 2 mL of 1N hydrochloric acid was added and the mixture was stirred for an additional 15 minutes and then separated by preparative HPLC (Method 7). This gave 118 mg (41% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.05 min; m / z = 494 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 2.26-2.46 (m, 2H), 2.73-2.85 (m, 1H ), 2.95-3.10 (m, 1H), 3.44 (s, 3H), 3.77 (s, 3H), 4.09-4.27 (m, 2H), 6.25- 6.57 (m, 1H), 6.74 (d, 1H), 6.78 (d, 1H), 7.12 (t, 1H), 7.35-7.64 (m, 2H), 7 .83 (br.s, 1H), 8.38 (s, 1H).

Example 234
3- (4-Methoxy-2,3-dihydro-1H-inden-1-yl) -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemate)

  115 mg (0.23 mmol) of the compound from Example 233 in 7.2 mL of glacial acetic acid / concentrated hydrochloric acid 2: 1 (volume ratio) was heated to reflux for 1 hour. After cooling to room temperature, the entire reaction mixture was separated by preparative HPLC (Method 7). This gave 42 mg (39% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.03 min; m / z = 466 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 2.26-2.38 (m, 1H), 2.44-2.56 (m, 1H), 2.78-2.89 (M, 1H), 3.07-3.19 (m, 1H), 3.38 (s, 3H), 3.75 (s, 3H), 6.46-6.58 (m, 1H), 6.62-6.73 (m, 2H), 7.02-7.14 (m, 2H), 7.18-7.28 (m, 1H), 7.37 (br.s, 1H), 8.44 (s, 1H).

Example 235
3- (4,6-Difluoro-2,3-dihydro-1H-inden-1-yl) -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazole-6 Yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemic)

  170 mg (0.34 mmol) of the compound from Example 108 in 7 mL of glacial acetic acid and 3.5 mL of concentrated hydrochloric acid was heated to reflux for 1 hour. After cooling to room temperature, the reaction mixture was purified by preparative HPLC (Method 7). This gave 133 mg (83% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.07 min; m / z = 472 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 2.2-2.45 (m, 1H), 2.52-2.64 (m, 1H), 2.84-2.97 (M, 1H), 3.14-3.26 (m, 1H), 3.38 (s, 3H), 6.44-6.56 (m, 1H), 6.58-6.70 (m 2H), 7.07 (d, 1H), 7.23 (d, 2H), 7.37 (br.s, 1H), 8.46 (s, 1H).

Example 236
3- (6-Methyl-2,3-dihydro-1H-inden-1-yl) -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemate)

  Compound Example 109 from 127 mg (0.27 mmol) was hydrolyzed under alkaline conditions as in Example 232 to purify the product. This gave 56 mg (47% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.10 min; m / z = 450 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 2.22 (s, 3H), 2.28-2.39 (m, 1H), 2.43-2.55 (m, 1H ), 2.82-2.94 (m, 1H), 3.12-3.24 (m, 1H), 3.38 (s, 3H), 6.44-6.55 (m, 1H), 6.86 (s, 1H), 6.98 (d, 1H), 7.02-7.12 (m, 2H), 7.24 (d, 1H), 7.38 (br.s, 1H) 8.45 (s, 1H).

Example 237
3- [6-Chloro-4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H -Benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

  Analogously to Example 233, 200 mg (0.58 mmol) of the compound from Example 2A was reacted with 179 mg (0.76 mmol) of 6-chloro-4- (trifluoromethyl) indan-1-ol from Example 108A. And the product was isolated. This gave 260 mg (69% of theory) of the title compound with a purity of 87%.

LC-MS (Method 1): Rt = 1.14 min; m / z = 563 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (br.t, 3H), 2.36-2.55 (m, 2H, partially hidden by DMSO signal ), 3.00-3.14 (m, 1H), 3.14-3.29 (m, 1H), 3.31 (s, 3H), 3.37 (s, 3H), 4.13- 4.25 (m, 2H), 6.29-6.54 (m, 1H), 7.18-7.31 (m, 2H), 7.39 (br.s, 1H), 7.59 ( s, 1H), 7.68 (br.s, 1H), 8.34 (s, 1H).

Example 238
3- [6-Chloro-4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H -Benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemic)

  In the same manner as in Example 217, 260 mg (0.46 mmol) of the compound from Example 237 was hydrolyzed and the product was isolated. This gave 200 mg (79% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.09 min; m / z = 535 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 2.35-2.46 (m, 1H), 2.58 (s, 1H), 3.00-3.12 (m, 1H) ), 3.31 (s, 3H), 3.33 (s, 3H), 3.35-3.44 (m, 1H), 6.49-6.60 (m, 1H), 6.87 ( s, 1H), 6.96 (s, 2H), 7.27 (s, 1H), 7.45 (s, 1H), 8.50 (s, 1H).

Example 239
3- [6-Bromo-4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H -Benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

  Analogously to Example 233, 226 mg (0.66 mmol) of the compound from Example 2A was reacted with 240 mg (0.85 mmol) of 6-bromo-4- (trifluoromethyl) indan-1-ol from Example 113A. And the product was isolated. This gave 230 mg (58% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.17 min; m / z = 607/609 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.23 (t, 2H), 2.28-2.43 (m, 1H), 2.52 (dtd, 1H); 00 (dt, 1H), 3.31 (s, 3H), 3.33 (s, 2H), 3.29-3.41 (m, 1H, partially hidden by methyl signal), 4 .21 (q, 2H), 6.42-6.65 (m, 1H), 6.88 (br.s, 1H), 6.96 (s, 2H), 7.40 (s, 1H), 7.54 (s, 1H), 8.24 (s, 1H).

Example 240
3- [6-Bromo-4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H -Benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemic)

  In the same manner as in Example 217, 52 mg (86 μmol) of the compound from Example 238 was hydrolyzed and the product was isolated. This gave 23 mg (46% of theory) of the title compound.

LC-MS (Method 5): Rt = 1.15 min; m / z = 579 (M + H) ^<+> .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 2.41-2.54 (m, 1H), 2.61-2.74 (m, 1H), 3.06-3.18 (M, 1H), 3.39 (s, 3H), 3.42 (s, 3H), 3.43-3.51 (m, 1H), 6.57-6.69 (m, 1H), 6.95 (s, 1H), 7.05 (s, 2H), 7.50 (s, 1H), 7.67 (s, 1H), 8.58 (s, 1H),
Example 241
1- [1-Methyl-2-oxo-3- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-benzimidazol-5-yl] -2,4-dioxo-3- [ (1R) -4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (R enantiomer)

  In the same manner as in Example 217, 370 mg (0.62 mmol) of the compound from Example 28 was hydrolyzed and the product was isolated. This gave 314 mg (89% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.15 min; m / z = 569 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 2.2-2.46 (m, 1H), 2.51-2.65 (m, 1H), 3.03-3.17 (M, 1H), 3.36 (s, 3H), 3.40-3.48 (m, 1H), 4.41 (q, 2H), 6.51-6.63 (m, 1H), 6.96 (s, 1H), 7.00-7.09 (m, 2H), 7.21-7.30 (m, 2H), 7.46 (d, 1H), 8.48 (s, 1H).

Example 242
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [6-fluoro-4- (trifluoromethyl) -2,3-dihydro- 1H-Inden-1-yl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemic)

  Analogously to Example 217, 63 mg (115 μmol) of the compound from Example 110 was hydrolyzed and the product was isolated. This gave 47 mg (78% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.09 min; m / z = 519 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 2.44-2.57 (m, 1H), 2.63-2.76 (m, 1H), 3.07-3.19 (M, 1H), 3.39 (s, 3H), 3.42 (s, 3H), 3.43-3.50 (m, 1H), 6.56-6.68 (m, 1H), 6.94 (s, 1H), 7.01-7.10 (m, 3H), 7.23-7.30 (m, 1H), 8.58 (s, 1H), 12.36 (br. s, 1H).

Example 243
1- (1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3-[(1R) -4- (trifluoromethyl) -2, 3-Dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (R enantiomer)

  In the same manner as in Example 217, 600 mg (1.17 mmol) of the compound from Example 112 was hydrolyzed (reaction time 4 hours), and the product was isolated. This gave 540 mg (89% of theory) of the title compound.

LC-MS (Method 3): Rt = 2.20 min; m / z = 487 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 2.2-2.45 (m, 1H), 2.51-2.64 (m, 1H), 3.02-3.17 (M, 1H), 3.31 (s, 3H), 3.36-3.47 (m, 1H), 6.52-6.61 (m, 1H), 6.96 (s, 3H), 7.21-7.31 (m, 2H), 7.42-7.50 (m, 1H), 8.14 (s, 1H), 8.47 (s, 1H), 12.36 (br. s, 1H).

Example 244
1- (3-Ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3-[(1R) -4- (trifluoromethyl ) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (R enantiomer)

  Analogously to Example 217, 73 mg (0.14 mmol) of the compound from Example 113 was hydrolyzed and the product was isolated. This gave 58 mg (82% of theory) of the title compound.

LC-MS (Method 3): Rt = 2.36 min; m / z = 515 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.22 (t, 3H), 2.33-3.45 (m, 1H), 2.52-2.64 (m, 1H) ), 3.04-3.17 (m, 1H), 3.33 (s, 3H), 3.37-3.48 (m, 1H), 3.83 (q, 2H), 6.51- 6.61 (m, 1H), 6.87 (s, 1H), 6.92-7.01 (m, 2H), 7.21-7.31 (m, 2H), 7.46 (d, 1H), 8.49 (s, 1H), 12.35 (br.s, 1H).

Example 245
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-3- [7- (trifluoromethyl) -2,3- Dihydro-1-benzofur-3-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemate)

  Analogously to Example 234, 32 mg (60 μmol) of the compound from Example 119 was hydrolyzed and the product was isolated. This gave 19 mg (63% of theory) of the title compound.

LC-MS (Method 5): Rt = 1.04 min; m / z = 506 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 3.38 (s, 3H), 4.74-4.88 (m, 2H), 6.79 (dd, 1H), 6. 91 (t, 1H), 7.07 (d, 1H), 7.21 (dd, 1H), 7.33 (d, 1H), 7.37 (d, 1H), 7.41 (d, 1H) ), 8.47 (s, 1H), 11.67-12.36 (br.s., 1H).

Example 246
1- [1-Methyl-2-oxo-3- (3,3,3-trifluoro-2-hydroxypropyl) -2,3-dihydro-1H-benzimidazol-5-yl] -2,4-dioxo -3-[(1R) -4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (diastereomer) blend)

  Analogously to Example 217, 180 mg (0.29 mmol) of the compound from Example 115 was hydrolyzed and the product was isolated. This gave 152 mg (83% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.11 min; m / z = 599 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 2.2-2.46 (m, 1H), 2.52-2.65 (m, 1H), 3.03-3.16 (M, 1H), 3.37 (s, 3H), 3.42-3.51 (m, 1H), 3.99-4.08 (m, 1H), 4.16 (d, 1H), 4.22-4.37 (m, 2H), 6.50-6.64 (m, 1H), 7.03 (d, 3H), 7.20-7.32 (m, 2H), 7. 46 (d, 1H), 8.47 (s, 1H), 12.29 (br.s, 1H).

Example 247
1- [1-Methyl-2-oxo-3- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-benzimidazol-5-yl] -2,4-dioxo-3- [ (1R) -4- (trifluoromethyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (R enantiomer)

  Analogously to Example 217, 160 mg (0.26 mmol) of the compound from Example 116 was hydrolyzed and the product was isolated. This gave 140 mg (91% of theory) of the title compound.

LC-MS (Method 5): Rt = 1.16 min; m / z = 583 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 2.47-2.58 (m, 1H), 2.60-2.77 (m, 3H), 3.17-3.29 (M, 1H), 3.47 (s, 3H), 3.49-3.61 (m, 1H), 4.16 (t, 2H), 6.63-6.76 (m, 1H), 7.00 (s, 1H), 7.08-7.16 (m, 2H), 7.35-7.44 (m, 2H), 7.59 (d, 1H), 8.61 (s, 1H), 12.46 (br.s, 1H).

Example 248
1- (3-Cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3-[(1R) -4- (trifluoro Methyl) -2,3-dihydro-1H-inden-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (R enantiomer)

  In the same manner as in Example 234, 160 mg (0.26 mmol) of the compound from Example 117 was hydrolyzed. The reaction mixture was diluted with 5 mL of acetonitrile and purified by preparative HPLC (Method 7). This gave 140 mg (91% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.07 min; m / z = 527 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 0.84-0.93 (m, 2H), 0.95-1.03 (m, 2H), 2.34-2.48 (M, 1H), 2.52-2.64 (m, 1H), 2.73-2.83 (m, 1H), 3.05-3.16 (m, 1H), 3.28 (s 3H), 3.36-3.49 (m, 1H), 6.51-6.63 (m, 1H), 6.89-6.99 (m, 2H), 7.06 (s, 1H) ), 7.21-7.32 (m, 2H), 7.46 (d, 1H), 8.49 (s, 1H).

Example 249
3- (4,6-Dichloro-2,3-dihydro-1H-inden-1-yl) -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazole-6 Yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

  First, under argon, 101 mg (0.29 mmol) of the compound from Example 31A, 71 mg (0.35 mmol) of 4,6-dichloroindan-1-ol from Example 114A and 137 mg (0.52 mmol) of triphenylphosphine. ) Was added to 8 mL of THF / DMF 1: 1 (volume ratio), and 97 μL (0.49 mmol) of diisopropyl azodicarboxylate was added dropwise. The mixture was stirred at room temperature for 1 hour. While cooling with ice, 2 mL of 1N hydrochloric acid was added and the mixture was stirred for an additional 15 minutes and then completely purified by preparative HPLC (Method 7). This gave 101 mg (65% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.20 min; m / z = 532 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.36 (t, 3H), 2.37-2.52 (m, 1H), 2.63 (dtd, 1H), 2. 93-3.08 (m, 1H), 3.25-3.40 (m, 1H), 3.51 (s, 3H), 4.34 (q, 2H), 6.65 (br.s, 1H), 7.09 (s, 1H), 7.19 (d, 1H), 7.29 (s, 1H), 7.36 (d, 1H), 7.50 (br.s, 1H), 8.34 (s, 1H).

Example 250
3- (4,6-Dichloro-2,3-dihydro-1H-inden-1-yl) -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazole-6 Yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemic)

  Analogously to Example 217, 106 mg (0.20 mmol) of the compound from Example 249 was hydrolyzed and the product was isolated. This gave 74 mg (73% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.17 min; m / z = 505 (M + H) ⁺ .

¹ H NMR (500 MHz, CD ₂ Cl ₂ ): δ [ppm] = 2.37-2.51 (m, 1H), 2.60-2.70 (m, 1H), 2.95-3.06 (M, 1H), 3.24-3.36 (m, 1H), 3.47 (s, 3H), 6.54-6.71 (m, 1H), 7.07 (s, 1H), 7.12-7.20 (m, 1H), 7.29 (s, 1H), 7.31-7.38 (m, 1H), 7.41-7.54 (m, 1H), 8. 56 (s, 1H).

Example 251
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- {1- [2-methyl-3- (trifluoromethyl) phenyl] ethyl} -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl (racemate)

  First, under argon, 250 mg (0.73 mmol) of the compound from Example 2A, 198 mg of 1- [2-methyl-3- (trifluoromethyl) phenyl] ethanol from Example 115A (purity 90%, 0.03 mmol). 87 mmol) and 324 mg (1.23 mmol) of triphenylphosphine were placed in 6.5 mL of THF / DMF 1: 2 (volume ratio), and 229 μL (1.16 mmol) of diisopropyl azodicarboxylate was added dropwise. The mixture was stirred at room temperature for 1 hour. While cooling with ice, 1 mL of 1N hydrochloric acid was added and the mixture was stirred for an additional 10 minutes and then purified by preparative HPLC (Method 7). This gave 153 mg (40% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.05 min; m / z = 531 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.30 (t, 3H), 1.87 (d, 3H), 2.34 (s, 3H), 3.38 (s, 3H), 3.40 (s, 3H), 4.27 (q, 2H), 6.30 (q, 1H), 6.90 (d, 1H), 6.95-7.07 (m, 2H) ), 7.31 (t, 1H), 7.58 (d, 1H), 7.92 (d, 1H), 8.28 (s, 1H).

Example 252
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- {1- [2-methyl-3- (trifluoromethyl) phenyl] ethyl} -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemate)

  In the same manner as in Example 217, 140 mg (0.26 mmol) of the compound from Example 251 was hydrolyzed and the product was isolated. This gave 79 mg (58% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.08 min; m / z = 503 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.92 (d, 3H), 2.35 (s, 3H), 3.38 (s, 3H), 3.41 (s, 3H), 6.35 (q, 1H), 6.90 (d, 1H), 6.97-7.05 (m, 2H), 7.34 (t, 1H), 7.62 (d, 1H) ), 7.93 (d, 1H), 8.53 (s, 1H), 12.5 (br.s, 1H).

  The product was separated into its enantiomers by preparative HPLC on chiral phase (Method 16). See Examples 253 and 254.

Example 253
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- {1- [2-methyl-3- (trifluoromethyl) phenyl] ethyl} -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (enantiomer 1)

  The first enantiomer eluting from a preparative separation of 65 mg of the compound from Example 252 according to Method 16. After drying under HV, 25 mg of the title compound was obtained.

  Chiral analytical HPLC (Method 17): Rt = 10.6 min.

Example 254
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- {1- [2-methyl-3- (trifluoromethyl) phenyl] ethyl} -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (enantiomer 2)

  Enantiomer last eluted from a preparative separation of 65 mg of the compound from Example 252 according to Method 16. After drying under HV, 28 mg of the title compound were obtained.

  Chiral analytical HPLC (Method 17): Rt = 11.5 min.

Example 255
3- {1- [2-Chloro-3- (trifluoromethyl) phenyl] ethyl} -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl (racemate)

  In the same manner as in Example 251, 500 mg (1.51 mmol) of the compound from Example 28A was converted to 508 mg of 1- [2-chloro-3- (trifluoromethyl) phenyl] ethanol from Example 116A (purity 80%, 1 .81 mmol) to purify the product. This gave 435 mg (54% of theory) of the title compound.

LC-MS (Method 4): Rt = 2.38 min; m / z = 538 (M + H) ⁺ .

¹ H NMR (500 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.2-1.35 (m, 3H), 1.87 (d, 3H), 3.40 (s, 3H), 4. 26 (q, 2H), 6.30 (q, 1H), 7.05 (d, 1H), 7.11-7.17 (m, 1H), 7.20 (d, 1H), 7.42 (T, 1H), 7.67 (d, 1H), 7.97 (d, 1H), 8.23 (s, 1H).

Example 256
3- {1- [2-Chloro-3- (trifluoromethyl) phenyl] ethyl} -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemate)

  Analogously to Example 217, 400 mg (0.74 mmol) of the compound from Example 255 was hydrolyzed and the product was isolated. This gave 320 mg (84% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.04 min; m / z = 510 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.91 (d, 3H), 3.41 (s, 3H), 6.37 (q, 1H), 7.05-7. 09 (m, 1H), 7.15 (dd, 1H), 7.21 (d, 1H), 7.45 (t, 1H), 7.71 (d, 1H), 7.97 (d, 1H) ), 8.50 (s, 1H), 12.37 (br.s, 1H).

  The product was separated into its enantiomers by preparative HPLC in chiral phase (Method 18). See Examples 257 and 258.

Example 257
3- {1- [2-Chloro-3- (trifluoromethyl) phenyl] ethyl} -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (enantiomer 1)

  The first enantiomer eluted from a preparative separation of 300 mg of the compound from Example 256 according to Method 18. After drying under HV, 129 mg of the title compound were obtained.

  Chiral analytical HPLC (Method 19): Rt = 74 min.

Example 258
3- {1- [2-Chloro-3- (trifluoromethyl) phenyl] ethyl} -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (enantiomer 2)

  Enantiomer last eluted from a preparative separation of 300 mg of the compound from Example 256 according to Method 18. After drying under HV, 128 mg of the title compound was obtained.

  Chiral analytical HPLC (Method 19): 16.6 min.

Example 259
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -3- {1- [2-methyl-3- (trifluoromethyl) phenyl] ethyl} -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl (racemate)

  In the same manner as in Example 251, 500 mg (1.51 mmol) of the compound from Example 28A was converted to 411 mg of 1- [2-methyl-3- (trifluoromethyl) phenyl] ethanol from Example 115A (purity 90%, 1 .81 mmol) to purify the product. This gave 285 mg (36% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.09 min; m / z = 518 (M + H) ⁺ .

¹ H NMR (500 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.30 (t, 3H), 1.86 (d, 3H), 2.33 (s, 3H), 3.40 (s, 3H), 4.27 (q, 2H), 6.29 (q, 1H), 7.04 (d, 1H), 7.10-7.15 (m, 1H), 7.18 (d, 1H) ), 7.31 (t, 1H), 7.58 (d, 1H), 7.91 (d, 1H), 8.24 (s, 1H).

Example 260
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -3- {1- [2-methyl-3- (trifluoromethyl) phenyl] ethyl} -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemate)

  In the same manner as in Example 217, 260 mg (0.50 mmol) of the compound from Example 259 was hydrolyzed and the product was isolated. This gave 200 mg (81% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.07 min; m / z = 490 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.91 (d, 3H), 2.34 (s, 3H), 3.41 (s, 3H), 6.35 (q, 1H), 7.07 (d, 1H), 7.14 (dd, 1H), 7.20 (d, 1H), 7.34 (t, 1H), 7.62 (d, 1H), 7. 92 (d, 1H), 8.51 (s, 1H), 12.43 (br.s, 1H).

  The product could be separated into its enantiomers by preparative HPLC in chiral phase (Method 20). See Examples 261 and 262.

Example 261
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -3- {1- [2-methyl-3- (trifluoromethyl) phenyl] ethyl} -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (enantiomer 1)

  The enantiomer first eluted from the preparative separation of 190 mg of the compound from Example 256 by Method 20. After drying under HV, 80 mg of the title compound was obtained.

  Chiral analytical HPLC (Method 21): Rt = 6.61 min.

Example 262
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -3- {1- [2-methyl-3- (trifluoromethyl) phenyl] ethyl} -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (enantiomer 2)

  Enantiomer last eluted from the preparative separation of 190 mg of the compound from Example 256 according to Method 20. After drying under HV, 82 mg of the title compound were obtained.

  Chiral analytical HPLC (Method 21): Rt = 10.6 min.

Example 263
1- (6-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  1- (6-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2 from Example 184 , 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate starting from 130 mg (0.26 mmol), the title compound was prepared and purified as in Example 121. The resulting crude product was purified by preparative HPLC (Method 8). The concentrated product fraction was stirred with dichloromethane and the solid was filtered and dried in vacuo. There was thus obtained 67 mg (51% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.95 min; m / z = 475 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.09 (s, 3H), 2.46 (s, 3H), 5.04-5.17 (m, 2H), 6. 88 (s, 1H), 7.10 (s, 1H), 7.36 (s, 2H), 7.58-7.62 (m, 1H), 8.37 (s, 1H), 10.77 -10.83 (m, 2H), 12.72 (br.s, 1H).

Example 264
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was produced and purified in the same manner as in Example 121 with the reaction time being 1.5 hours. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2 from Example 185 Starting from 150 mg (0.29 mmol) of ethyl 1,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 126 mg (84% of theory) of the title compound were obtained.

LC-MS (Method 1): Rt = 0.96 min; m / z = 495 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.10 (s, 3H), 5.17 (s, 2H), 6.88 (s, 1H), 7.10 (s, 1H), 7.50-7.60 (m, 2H), 7.78-7.83 (m, 1H), 8.39 (s, 1H), 10.80 (s, 2H), 12.69 (Br.s, 1H).

Example 265
3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -2 , 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  The title compound was produced and purified in the same manner as in Example 121, with the reaction time being 30 minutes. 3- [2-Chloro-3- (trifluoromethyl) benzyl] -1- (1-ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indole-6 from Example 208 Starting from 50 mg (0.09 mmol) of ethyl -yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 26 mg (54% of theory) of the title compound were obtained. .

LC-MS (Method 3): Rt = 1.37 min; m / z = 536 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.1-1.19 (m, 3H), 1.30 (s, 6H), 3.65-3.75 (m, 2H ), 5.18 (s, 2H), 7.17-7.23 (m, 1H), 7.31 (s, 1H), 7.48-7.57 (m, 2H), 7.57- 7.63 (m, 1H), 7.77-7.85 (m, 1H), 8.52 (s, 1H), 12.73 (br.s, 1H).

Example 266
1- (4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2, 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl

  1- (4-Methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -2,4-dioxo-1,2,3,4 from Example 119A Preparation and purification were carried out as in Example 216 starting from 200 mg (0.58 mmol) of ethyl tetrahydropyrimidine-5-carboxylate and 147 mg (0.58 mmol) of 2-methyl-3- (trifluoromethyl) benzyl bromide. went. This gave 168 mg (53% of theory) of the title compound.

LC-MS (Method 3): Rt = 1.26 min; m / z = 518 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22 (t, 3H), 2.46 (s, 3H), 3.30 (s, partially hidden by water signal 3H), 4.20 (q, 2H), 4.71 (s, 2H), 5.06 (s, 2H), 7.22-7.32 (m, 3H), 7.32-7 .41 (m, 2H), 7.59 (d, 1H), 8.39 (s, 1H).

Example 267
3- (2-Methyl-3-nitrobenzyl) -1- (4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  185 mg (0.58 mmol) of the compound from Example 216 was dissolved in 5 mL of glacial acetic acid and 2.5 mL of concentrated hydrochloric acid and stirred at 60 ° C. for 6 hours. After cooling to room temperature, add 75 mL water. The precipitated solid was filtered, washed with and dried under water and HV. This gave 129 mg (70% of theory) of the title compound.

LC-MS (Method 1): Rt = 0.96 min; m / z = 467 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.41 (s, 3H), 3.30 (s, 3H partially hidden by water signal), 4.72 ( s, 2H), 5.10 (s, 2H), 7.22-7.32 (m, 3H), 7.37 (t, 1H), 7.44 (d, 1H), 7.72 (d 1H), 8.41 (s, 1H), 12.71 (br.s, 1H).

Example 268
1- (4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -3- [2-methyl-3- (trifluoromethyl) benzyl] -2, 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

  130 mg (0.25 mmol) of the compound from Example 267 was dissolved in 5 mL of glacial acetic acid and 2.5 mL of concentrated hydrochloric acid and stirred at 60 ° C. for 6 hours. After cooling to room temperature, 75 mL of water was added. The precipitated solid was filtered, washed with water and dried under HV. This gave 109 mg (89% of theory) of the title compound.

LC-MS (Method 1): Rt = 1.09 min; m / z = 490 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 2.48 (s, 3H), 3.30 (s, 3H partially hidden by water signal), 4.72 ( s, 2H), 5.10 (s, 2H), 7.22-7.42 (m, 5H), 7.60 (d, 1H), 8.42 (s, 1H), 12.70 (br) .S, 1H).

Example 269
3- (5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl ) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

  1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid Ethyl (Example 2A) 400 mg (1.16 mmol), 5-chloro-1,2,3,4-tetrahydronaphthalen-1-ol 255 mg (1.39 mmol) and triphenylphosphine 518 mg (1.98 mmol) in THF 5 mL And dissolved in 10 mL DMF. 376 mg (1.86 mmol) of DIAD was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was mixed with a small amount of 1M aqueous hydrochloric acid and completely separated by preparative HPLC (Method 15). This gave 510 mg (86% of theory) of the title compound.

LC / MS (Method 1): Rt = 1.09; m / z = 509 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.23 (t, 3H), 1.61-1.80 (m, 1H), 1.92-2.12 (m, 2H ), 2.24-2.44 (m, 1H), 2.53-2.72 (m, 1H), 2.94 (br.d, 1H), 3.30 (s, 3H), 3. 32 (s, 3H), 4.21 (br.q, 2H), 6.16 (br.s., 1H), 6.85 (d, 2H), 6.89-7.02 (m, 3H) ), 7.13 (d, 1H), 8.25 (s, 1H).

Example 270
3- (5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl ) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemic)

  3- (5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzine from Example 269 490 mg (0.96 mmol) of ethyl imidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate was stirred in 3 mL of concentrated hydrochloric acid and 7 mL of glacial acetic acid at reflux temperature. When the conversion was complete, the reaction mixture was cooled and separated directly by preparative HPLC (Method 15). This gave 369 mg (80% of theory) of the title compound.

LC / MS (Method 1): Rt = 1.10 min; m / z = 481 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.74-1.91 (m, 1H), 2.07-2.24 (m, 2H), 2.44 (q, 1H) ) 2.63-2.84 (m, 1H), 3.05 (d, 1H), 3.39 (s, 3H), 3.41 (s, 3H), 6.27 (br.s. 1H), 6.84-6.98 (m, 2H), 6.98-7.15 (m, 3H), 7.25 (d, 1H), 8.59 (s, 1H), 12. 5 (br.s, 1H).

Example 271
3- (5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl ) -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

  3- (5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzine from Example 270 680 μL (9.36 mmol) thionyl chloride in a solution of 300 mg (0.62 mmol) of imidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid in methanol (5 mL) Was added. The mixture was stirred at reflux temperature for 7 hours and then concentrated on a rotary evaporator. The residue was dried under high vacuum. This gave 302 mg (94% of theory) of the title compound.

LC / MS (Method 28): Rt = 3.10 min; m / z = 495 (M + H) ⁺ .

Example 272
3- (5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl ) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (enantiomer 1)

  Enantiomer (56 mg) eluting first from the separation of 300 mg of racemic material from Example 271 by preparative HPLC of chiral phase (Method 29).

  Chiral analytical HPLC (Method 30): Rt = 6.14 min,> 99% ee.

  The resulting product was purified by preparative HPLC (Method 15) to remove solvent impurities. This gave 49 mg of the title compound.

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.72-1.87 (m, 1H), 2.01-2.20 (m, 2H), 2.33-2.50 (M, 1H), 2.62-2.79 (m, 1H), 3.03 (d, 1H), 3.38 (s, 3H), 3.41 (s, 3H), 3.82 ( br.s., 3H), 6.23 (br.s., 1H), 6.85-7.13 (m, 5H), 7.21 (d, 1H), 8.36 (s, 1H) .

Example 273
3- (5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl ) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (enantiomer 2)

  Enantiomer (92 mg) eluting last from the separation of 300 mg of racemic material from Example 271 by preparative HPLC of chiral phase (Method 29).

  Chiral analytical HPLC (Method 30): Rt = 7.29 min, 97% ee.

  The resulting product was purified by preparative HPLC (Method 15) to remove solvent impurities. This gave 68 mg of the title compound.

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ππμ] = 1.73-1.88 (μ, 1H), 2.01-2.21 (μ, 2H), 2.33-2.51 (Μ, 1H), 2.62-2.80 (μ, 1H), 2.03 (δ, 1H), 3.38 (σ, 3H), 3.41 (σ, 3H), 3.82 ( βρ.σ., 3H), 6.24 (βρ.σ., 1H), 6.84-7.11 (μ, 5H), 7.21 (δ, 1H), 8.36 (σ, 1H) .

Example 274
3- (5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl ) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (enantiomer 1)

  3- (5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzine from Example 272 47 mg (0.10 mmol) of methyl (imidazole-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Enantiomer 1) was added to glacial acetic acid / concentrated hydrochloric acid (2: 1 volume). Ratio) The mixture was stirred at reflux temperature in 2 mL for 2 hours. The reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in acetonitrile / water and lyophilized. This gave 38 mg (76% of theory) of the title compound.

LC / MS (Method 1): Rt = 1.08 min; m / z = 481 (M + H) ⁺ .

Example 275
3- (5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl ) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (enantiomer 2)

  3- (5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzine from Example 273 66 mg (0.13 mmol) of methyl imidazol-5-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (enantiomer 2) were added to glacial acetic acid / concentrated hydrochloric acid (2: 1 volume). Ratio) The mixture was stirred at reflux temperature in 2 mL for 2 hours. The reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in acetonitrile / water and lyophilized. This gave 62 mg (87% of theory) of the title compound.

LC / MS (Method 1): Rt = 1.08 min; m / z = 481 (M + H) ⁺ .

Example 276
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [5- (trifluoromethyl) -1,2, 3,4-Tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

  1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-1,2,3,4-in 3 mL of THF and 6 mL of DMF 225 mg (0.66 mmol) of ethyl tetrahydropyrimidine-5-carboxylate (Example 2A), 170 mg (0.79 mmol) of 5- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-ol and tri 292 mg (1.11 mmol) of phenylphosphine was mixed with 212 mg (1.05 mmol) of DIAD at room temperature. The mixture was stirred at room temperature for 2 hours, then mixed with a small amount of 1M aqueous hydrochloric acid, diluted with DMSO and purified by preparative HPLC (Method 15). This gave 136 mg (38% of theory) of the title compound.

LC / MS (Method 1): Rt = 1.14 min; m / z = 543 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.23 (t, 3H), 1.65 to 1.80 (m, 1H), 1.99-2.11 (m, 2H) ), 2.25-2.41 (m, 1H), 2.74-2.92 (m, 1H), 2.99 (d, 1H), 3.30 (s, 3H), 3.32 ( s, 3H), 4.21 (q, 2H), 6.20 (br.s., 1H), 6.78-7.00 (m, 3H), 7.09-7.18 (m, 2H) ), 7.40 (t, 1H), 8.25 (s, 1H).

Example 277
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [5- (trifluoromethyl) -1,2, 3,4-Tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemic)

  1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [5- (trifluoromethyl) from Example 276 -1,2,3,4-Tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate 120 mg (0.22 mmol) refluxed with 2 mL of concentrated hydrochloric acid and 4 mL of glacial acetic acid Stir at temperature for 2 hours. The reaction mixture was diluted with 5 mL of acetonitrile and purified by preparative HPLC (Method 15). This gave 54 mg (47% of theory) of the title compound.

LC / MS (Method 1): Rt = 1.12 min; m / z = 515 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.74-1.91 (m, 1H), 2.12-2.24 (m, 2H), 2.35-2.50 (M, 1H), 2.85-2.99 (m, 1H), 3.04-3.15 (m, 1H), 3.39 (s, 3H), 3.41 (s, 3H), 6.32 (br.s., 1H), 6.86-6.97 (m, 1H), 6.98-7.11 (m, 2H), 7.16-7.29 (m, 2H) 7.52 (d, 1H), 8.59 (s, 1H), 12.47 (br.s, 1H).

Example 278
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [5- (trifluoromethyl) -1,2, 3,4-Tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate methyl (racemate)

  1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [5- (trifluoromethyl) from Example 277 -1,2,3,4-tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid 45 mg (0.09 mmol) was dissolved in 5 mL of methanol, and 100 μL (1. 31 mmol) was added and the mixture was stirred at reflux for 5 hours. The reaction solution was concentrated under reduced pressure and the residue was dried under high vacuum. This gave 46 mg (92% of theory) of the title compound.

LC / MS (Method 28): Rt = 3.25 min; m / z = 529 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.70-1.90 (m, 1H), 2.07-2.19 (m, 2H), 2.31-2.49 (M, 1H), 2.83-3.00 (m, 1H), 3.07 (d, 1H), 3.40 (s, 3H), 3.42 (s, 3H), 3.82 ( s, 3H), 6.27 (br.s., 1H), 6.91-6.99 (m, 1H), 7.00-7.11 (m, 2H), 7.21 (d, 2H) ), 7.48 (t, 1H), 8.37 (s, 1H).

Example 279
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [5- (trifluoromethyl) -1,2, 3,4-Tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (enantiomer 1)

  Enantiomer eluting first (17 mg) from separation of 45 mg of racemic material from Example 278 by preparative HPLC in chiral phase (Method 31).

  Chiral analytical HPLC (Method 32): Rt = 4.14 min,> 99% ee.

LC / MS (Method 1): Rt = 1.06 min; m / z = 529 (M + H) ⁺ .

Example 280
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [5- (trifluoromethyl) -1,2, 3,4-tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (enantiomer 2)

  Enantiomer (19 mg) eluting last from the separation of 45 mg of racemic material from Example 278 by preparative HPLC in chiral phase (Method 31).

  Chiral analytical HPLC (Method 32): Rt = 4.68 min, 98% ee.

LC / MS (Method 1): Rt = 1.06 min; m / z = 529 (M + H) +
Example 281
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [5- (trifluoromethyl) -1,2, 3,4-Tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (enantiomer 1)

  14 mg (0.03 mmol) of the compound from Example 279 in glacial acetic acid / concentrated hydrochloric acid 2: 1 (volume ratio) (1.75 mL) was stirred at reflux temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in acetonitrile and water and lyophilized. This gave 7 mg (48% of theory) of the title compound.

LC / MS (Method 1): Rt: 1.10 min; m / z = 515 (M + H) ⁺ .

Example 282
1- (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,4-dioxo-3- [5- (trifluoromethyl) -1,2, 3,4-tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (enantiomer 2)

  16 mg (0.03 mmol) of the compound from Example 280 was stirred at reflux for 2 hours in 2 mL of a 2: 1 (volume ratio) mixture of glacial acetic acid / concentrated hydrochloric acid. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in acetonitrile and water and lyophilized. This gave 13 mg (76% of theory) of the title compound.

LC / MS (Method 1): Rt = 1.10 min; m / z = 515 (M + H) ⁺
Example 283
3- (5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl ) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

  First, 1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2,3,4 from Example 28A. -400 mg (1.21 mmol) of tetrahydropyrimidine-5-carboxylate, 265 mg (1.45 mmol) of 5-chloro-1,2,3,4-tetrahydronaphthalen-1-ol and 538 mg (2.05 mmol) of triphenylphosphine Was placed in 5 mL THF and 10 mL DMF at room temperature. 391 mg (1.93 mmol) of DIAD was added and the reaction mixture was stirred at room temperature for 2 hours. After addition of a small amount of 1M aqueous hydrochloric acid, the mixture was dissolved in DMSO and purified by preparative HPLC (Method 11). This gave 300 mg (47% of theory) of the title compound. Got.

LC / MS (Method 1): Rt = 1.13 min; m / z = 496 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.24 (t, 3H), 1.64-1.81 (m, 1H), 1.93-2.11 (m, 2H) ), 2.21-2.42 (m, 1H), 2.51-2.71 (m, 1H), 2.94 (d, 1H), 3.32 (s, 3H), 4.21 ( q, 2H), 6.14 (br.s., 1H), 6.83 (d, 1H), 6.97 (t, 2H), 7.13 (d, 3H), 8.22 (s, 1H).

Example 284
3- (5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl ) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemic)

  3- (5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoate from Example 283 270 mg (0.54 mmol) of ethyl oxazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate was stirred in 2 mL concentrated hydrochloric acid and 4 mL glacial acetic acid at reflux temperature. . After cooling, the mixture was purified by preparative HPLC (Method 15). This gave 200 mg (79% of theory) of the title compound.

LC / MS (Method 1): Rt = 1.14 min; m / z = 468 (M + H) ⁺ .

¹ HNMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.73-1.90 (m, 1H), 2.03-2.23 (m, 2H), 2.31-2.51 ( m, 1H), 2.62-2.80 (m, 1H), 3.05 (d, 1H), 3.41 (s, 3H), 6.27 (br.s., 1H), 6. 89 (d, 1H), 7.08 (t, 2H), 7.14-7.29 (m, 3H), 8.56 (s, 1H), 12.40 (br.s., 1H).

Example 285
3- (5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl ) -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

  50 mg (0.11 mmol) of the compound from Example 284 was dissolved in 5 mL of methanol and 117 μL (1.60 mmol) of thionyl chloride was added. The mixture was stirred at reflux temperature for 5 hours, then concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 51 mg (90% of theory) of the title compound.

LC / MS (Method 4): Rt = 2.42 min; m / z = 482 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.80 (q, 1H), 2.01-2.21 (m, 2H), 2.30-2.50 (m, 1H ) 2.63-2.79 (m, 1H), 3.03 (d, 1H), 3.41 (s, 3H), 3.83 (s, 3H), 6.06-6.41 ( m, 1H), 6.91 (d, 1H), 7.03-7.11 (m, 2H), 7.14-7.26 (m, 3H), 8.33 (s, 1H).

Example 286
3- (5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl ) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (enantiomer 1)

  Racemic 3- (5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (3-methyl-2-oxo-2, by preparative HPLC of chiral phase (Method 29) Methyl 3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 285) eluting first from a separation of 152 mg Enantiomer to do.

  Chiral analytical HPLC (Method 30): Rt = 4.44 min,> 99% ee.

  The resulting product was purified by preparative HPLC (Method 15) to remove solvent impurities. This gave 34 mg of the title compound.

LC / MS (Method 1): Rt = 1.08 min; m / z = 482 (M + H) ⁺ .

Example 287
3- (5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl ) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (enantiomer 2)

  Racemic 3- (5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (3-methyl-2-oxo-2, by preparative HPLC of chiral phase (Method 29) Methyl 3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 285) Elution last from 152 mg separation Enantiomer to do.

  Chiral analytical HPLC (Method 30): Rt = 5.87 min, 99% ee.

  The resulting product was purified by preparative HPLC (Method 15) to remove solvent impurities. This gave 27 mg of the title compound.

LC / MS (Method 1): Rt = 1.08 min; m / z = 482 (M + H) ⁺ .

Example 288
3- (5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl ) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (enantiomer 1)

  32 mg (66 μmol) of the compound from Example 286 in 2 mL of glacial acetic acid / concentrated hydrochloric acid 2: 1 (volume ratio) was stirred at reflux temperature for 2 hours. The mixture was concentrated by rotary evaporator, dissolved in acetonitrile and water and lyophilized. This gave 33 mg (purity 92%, 97% of theory) of the title compound.

LC / MS (Method 1): Rt = 1.12 min; m / z = 468 (M + H) ⁺ .

Example 289
3- (5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl) -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl ) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (enantiomer 2)

  25 mg (0.052 mmol) of the compound from Example 287 in 1.6 mL of glacial acetic acid / concentrated hydrochloric acid 2: 1 (volume ratio) was stirred at reflux temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in acetonitrile and water and lyophilized. This gave 24 mg (93% of theory) of the title compound.

LC / MS (Method 1): Rt = 1.12 min; m / z = 468 (M + H) ⁺ .

Example 290
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-3- [5- (trifluoromethyl) -1,2, 3,4-Tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

First, 1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5 -217 mg (0.66 mmol) of ethyl carboxylate (Example 28A), 170 mg (0.79 mmol) of 5- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-ol and 292 mg of triphenylphosphine ( 1.11 mmol) was placed in 3 mL THF and 6 mL DMF at room temperature. DIAD 212 mg (1.05 mmol) was added and the mixture was stirred at room temperature for 2 hours. After adding a small amount of 1M aqueous hydrochloric acid, the mixture was dissolved in DMSO and purified by preparative HPLC (Method 15). This gave 114 mg (33% of theory) of the title compound. .
LC / MS (Method 1): Rt = 1.18 min; m / z = 530 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.24 (t, 3H), 1.65 to 1.80 (m, 1H), 1.98-2.11 (m, 2H) ), 2.21-2.39 (d, 1H), 2.73-2.91 (d, 1H), 2.93-3.04 (m, 1H), 3.32 (s, 3H), 4.22 (q, 2H), 6.19 (br.s., 1H), 6.97 (d, 1H), 7.03-7.20 (m, 4H), 7.37-7.44 (M, 1H), 8.22 (s, 1H).

Example 291
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-3- [5- (trifluoromethyl) -1,2, 3,4-Tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemic)

  95 mg (0.18 mmol) of the compound from Example 290 was stirred with refluxing temperature for 2 hours with 2 mL of concentrated hydrochloric acid and 4 mL of glacial acetic acid. After cooling, the mixture was diluted with 5 mL of acetonitrile and purified by preparative HPLC (Method 15). This gave 83 mg (92% of theory) of the title compound.

LC / MS (Method 1): Rt = 1.15 min; m / z = 502 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.65-1.81 (m, 1H), 2.01-2.17 (m, 2H), 2.25-2.39 (M, 1H), 2.76-2.92 (m, 1H), 2.96-3.10 (m, 1H), 3.33 (s, 3H), 6.23 (br.s., 1H), 6.99 (d, 1H), 7.04-7.22 (m, 4H), 7.44 (d, 1H), 8.48 (s, 1H), 12.30 (br.s) 1H).

Example 292
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-3- [5- (trifluoromethyl) -1,2, 3,4-Tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate methyl (racemate)

  1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-3- [5- (trifluoromethyl) from Example 291 -1,2,3,4-tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid 60 mg (0.12 mmol) was dissolved in 5 mL of methanol, and 131 μL of thionyl chloride (1. 80 mmol) was added. The mixture was stirred at reflux temperature for 7 hours, then concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 60 mg (77% of theory) of the title compound with a purity of 79%.

LC / MS (Method 28): Rt = 3.40 min; m / z = 516 (M + H) ⁺ _.
Example 293
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-3- [5- (trifluoromethyl) -1,2, 3,4-Tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (enantiomer 1)

  Racemic 1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-3- [5- (tri Fluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate 60 mg (0.12 mmol) was dissolved in 3 mL of acetonitrile and 1 mL of ethanol. , 40% acetonitrile and 60% MTBE on a Daicel Chiralpak IC column. Partial transesterification to the ethyl ester occurred. As the first eluted fraction, 14.5 mg of the title compound was obtained.

  Chiral analytical HPLC (Method 30): Rt = 3.99 min, 99% ee.

LC / MS (Method 1): Rt = 1.11 min; m / z = 516 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.64-1.80 (m, 1H), 1.99-2.10 (m, 2H), 2.23-2.36 (M, 1H), 2.75-2.90 (m, 1H), 2.94-3.04 (m, 1H), 3.32 (s, 3H), 3.75 (s, 3H), 6.18 (br.s., 1H), 6.97 (d, 1H), 7.03-7.22 (m, 4H), 7.37-7.45 (m, 1H), 8.25 (S, 1H).

  The second eluting fraction gave a mixture (43 mg) of the epimer of the title compound and the two enantiomers of the corresponding ethyl ester. This mixture was not purified further.

Example 294
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-3- [5- (trifluoromethyl) -1,2, 3,4-Tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (enantiomer 1)

  1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-3- [5- (trifluoromethyl) from Example 293 -1,2,3,4-tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate 12 mg (0.02 mmol) in a ratio of glacial acetic acid and concentrated hydrochloric acid 2: 1 The mixture was stirred with 0.4 mL of the mixture at reflux temperature for 2 hours. The mixture was concentrated and the residue was dissolved in acetonitrile / water and then lyophilized. This gave 11 mg (91% of theory) of the title compound.

LC / MS (Method 1): Rt = 1.12 min; m / z = 502 (M + H) ⁺ .

Example 295
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-3- [5- (trifluoromethyl) -1,2, 3,4-Tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (racemate)

  First, 1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5 -227 mg (0.66 mmol) of ethyl carboxylate (Example 31A), 170 mg (0.79 mmol) of 5- (trifluoromethyl) -1,2,3,4-tetrahydronaphthalen-1-ol and triphenylphosphine 292. 2 mg (1.11 mmol) was placed in 3 mL THF and 6 mL DMF at room temperature. 206 μL (1.05 mmol) of DIAD was added and the reaction mixture was stirred at room temperature for 2 hours. After adding a small amount of 1M aqueous hydrochloric acid, the mixture was dissolved in DMSO and separated by preparative HPLC (Method 15). This gave 196 mg (52% of theory) of the title compound.

LC / MS (Method 1): Rt = 1.23 min; m / z = 546 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.24 (t, 3H), 1.65 to 1.80 (m, 1H), 1.99-2.11 (m, 2H) ), 2.23-2.38 (m, 1H), 2.75-2.90 (m, 1H), 2.94-3.05 (m, 1H), 3.37 (s, 3H), 4.22 (q, 2H), 6.20 (br.s., 1H), 7.05 (d, 1H), 7.12 (d, 2H), 7.15-7.28 (m, 1H) ), 7.29-7.46 (m, 2H), 8.23 (s, 1H).

Example 296
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-3- [5- (trifluoromethyl) -1,2, 3,4-Tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemic)

  120 mg (0.21 mmol) of the compound from Example 295 in 2 mL of glacial acetic acid and 4 mL of concentrated hydrochloric acid was stirred at reflux temperature for 2 hours. The reaction mixture was cooled, diluted with 5 mL of acetonitrile and purified by preparative HPLC (Method 15). This gave 85 mg (78% of theory) of the title compound.

LC / MS (Method 1): Rt = 1.18 min; m / z = 518 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.74-1.90 (m, 1H), 2.10-2.25 (m, 2H), 2.40 (q, 1H) ), 2.83-2.99 (m, 1H), 3.05-3.15 (m, 1H), 3.46 (s, 3H), 6.32 (br.s., 1H), 7 .11-7.20 (m, 2H), 7.21-7.35 (m, 2H), 7.44 (br.s., 1H), 7.52 (d, 1H), 8.57 ( s, 1H), 12.38 (br.s, 1H).

Example 297
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-3- [5- (trifluoromethyl) -1,2, 3,4-Tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate methyl (racemate)

  70 mg (0.14 mmol) of the compound from Example 296 was dissolved in 5 mL of methanol and 148 μL (2.03 mmol) of thionyl chloride was added. The mixture was stirred at reflux temperature for 7 hours, then concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 70 mg of the title compound with a purity of 75% (72% of theory).

LC / MS (Method 28): Rt = 3.59 min; m / z = 532 (M + H) ⁺ .

Example 298
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-3- [5- (trifluoromethyl) -1,2, 3,4-Tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (enantiomer 1)

  Enantiomer eluting first (24 mg) from separation of 70 mg of racemic material from Example 297 by preparative HPLC in chiral phase (Method 33).

  Chiral analytical HPLC (Method 34): Rt = 6.03 min, 99% ee.

LC / MS (Method 1): Rt = 1.16 min; m / z = 532 (M + H) ^+
1 H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.72-1.88 (m, 1H), 2.05-2.20 (m, 2H), 2.30-2.47 (M, 1H), 2.83-2.98 (m, 1H), 3.01-3.14 (m, 1H), 3.45 (s, 3H), 3.83 (s, 3H), 6.18-6.37 (m, 1H), 7.05-7.37 (m, 4H), 7.48 (d, 2H), 8.34 (s, 1H).

Example 299
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-3- [5- (trifluoromethyl) -1,2, 3,4-tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate (enantiomer 2)

  Enantiomer (29 mg) eluting last from the separation of 70 mg of racemic material from Example 297 by preparative HPLC in chiral phase (Method 33).

  Chiral analytical HPLC (Method 34): Rt = 7.37 min 99% ee.

LC / MS (Method 1): Rt = 1.16 min; m / z = 532 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.7-1.87 (m, 1H), 2.06-2.20 (m, 2H), 2.30-2.46 (M, 1H), 2.82-2.99 (m, 1H), 3.01-3.12 (m, 1H), 3.45 (s, 3H), 3.83 (s, 3H), 6.28 (br.s., 1H), 7.13 (d, 1H), 7.16-7.35 (m, 3H), 7.38-7.57 (m, 2H), 8.34 (S, 1H).

Example 300
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-3- [5- (trifluoromethyl) -1,2, 3,4-Tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (enantiomer 1)

  22 mg (0.04 mmol) of the compound from Example 298 was stirred at reflux temperature for 2 hours with 2 mL of glacial acetic acid / concentrated hydrochloric acid in a ratio of 2: 1 (volume ratio). The mixture was concentrated on a rotary evaporator and the residue was dissolved in acetonitrile / water and then lyophilized. This gave 16 mg (75% of theory) of the title compound.

LC / MS (Method 1): Rt = 1.16 min; m / z = 518 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.74-1.90 (m, 1H), 2.11-2.24 (m, 2H), 2.31-2.46 (M, 1H), 2.84-3.00 (m, 1H), 3.04-3.15 (m, 1H), 3.46 (s, 3H), 6.32 (br.s., 1H), 7.10-7.21 (m, 2H), 7.21-7.37 (m, 4H), 7.38-7.49 (m, 1H), 7.52 (d, 1H) 8.58 (s, 1H), 12.38 (br.s, 1H).

Example 301
1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl) -2,4-dioxo-3- [5- (trifluoromethyl) -1,2, 3,4-tetrahydronaphthalen-1-yl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (enantiomer 2)

  27 mg (0.05 mmol) of the compound from Example 299 in 2.5 mL of glacial acetic acid / concentrated hydrochloric acid was stirred at reflux temperature for 2 hours. The mixture was concentrated on a rotary evaporator and the residue was dissolved in acetonitrile / water and lyophilized. This gave 22 mg (81% of theory) of the title compound.

LC / MS (Method 1): Rt = 1.19 min; m / z = 518 (M + H) ⁺ .

Example 302
3- (8-Chloro-3,4-dihydro-1H-isochromen-4-yl) -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate ethyl (racemate)

  1- (3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-dioxo-1,2,3 from Example 28A under argon. 149.5 mg (0.45 mmol) of ethyl 4-tetrahydropyrimidine-5-carboxylate, 100.0 mg (0.54 mmol) of 8-chloro-3,4-dihydro-1H-isochromen-4-ol (Example 120A) and 201.3 mg (0.77 mmol) of triphenylphosphine was dissolved in 4.8 mL of DMF and 2.4 mL of THF. 146.0 mg (0.72 mmol) of DIAD was added dropwise and the reaction mixture was stirred at room temperature. After 2 hours, 5 mL of 1M aqueous hydrochloric acid was added and the mixture was separated by preparative HPLC (Method 15). This gave 59.0 mg (26% of theory) of the title compound.

LC / MS (Method 1): Rt = 1.02 min; m / z = 498 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 1.31 (t, 3H), 3.41 (s, 3H), 4.08-4.15 (m, 1H), 4. 22-4.35 (m, 3H), 4.74 (d, 1H), 4.93 (d, 1H), 6.26-6.38 (m, 1H), 7.00 (d, 1H) 7.03-7.08 (m, 1H), 7.13-7.26 (m, 4H), 8.31 (s, 1H).

Example 303
3- (8-Chloro-3,4-dihydro-1H-isochromen-4-yl) -1- (3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl) -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (racemate)

  50 mg (0.10 mmol) of the compound from Example 302 was heated in 6.7 mL of a concentrated hydrochloric acid / glacial acetic acid 1: 2 mixture at reflux temperature for 50 minutes. After cooling to room temperature, the entire mixture was separated by preparative HPLC (Method 15). This gave 10 mg (21% of theory) of the title compound.

LC / MS (Method 1): Rt = 0.98 min; m / z = 470 (M + H) ⁺ .

¹ H NMR (400 MHz, CD ₂ Cl ₂ ): δ [ppm] = 3.41 (s, 3H), 4.17 (dd, 1H), 4.22-4.30 (m, 1H), 4. 76 (d, 1H), 4.94 (d, 1H), 6.28-6.40 (m, 1H), 6.99 (d, 1H), 7.08 (d, 1H), 7.19 (T, 2H), 7.28 (d, 1H), 8.57 (s, 1H).

B. Evaluation of pharmacological efficacy The pharmacological action of the compounds of the present invention can be demonstrated by the following assay.

B-1. Enzyme Chymase Assay The enzyme source used is recombinant human chymase (expressed in HEK293 cells) or chymase purified from hamster tongue. The substrate used in the chymase is Abz-HPFHL-Lys (Dnp) -NH 2. The assay includes 1 μL of a 50-fold concentrated solution of the test substance in DMSO in assay buffer (Tris 50 mM, pH 7.5, sodium chloride 150 mM, BSA 0.10%, Chaps 0.10%, glutathione 1 mM, EDTA 1 mM), enzyme 24 μL of solution (dilution; human 1: 80000 or hamster 1: 4000) and 25 μL of substrate solution (final concentration 10 μM) were combined in a white 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany). The reaction is incubated for 60 minutes at 32 ° C., and fluorescence emission at 465 nm is measured with a fluorescence reader, eg, Tecan Ultra (Tecan, Mannedorf, Switzerland) after excitation at 340 nm.

One test compound is tested in the same microtiter plate at 10 different concentrations from 30 μM to 1 nM in duplicate measurements. Data are normalized (enzyme reaction without inhibitor = 0% inhibition, total assay components without enzyme = 100% inhibition) and IC ₅₀ values are calculated using in-house software. Compounds in the context of the present invention examined in this assay inhibited chymase activity with an IC ₅₀ of less than 10 μM.

IC ₅₀ values representative of the compounds of the present invention are shown in Tables 1 and 2 below.

B-2. Measurement of contraction in isolated aortic rings from hamsters Male Syrian hamsters (120-150 g) were sacrificed with carbon dioxide. An aorta was prepared and ice-cooled Krebs-Henseleit buffer (composition (unit: mmol / L): sodium chloride: 112, potassium chloride: 5.9, calcium chloride: 2.0, magnesium chloride: 1.2, Sodium dihydrogen phosphate: 1.2, sodium hydrogen carbonate: 25, glucose: 11.5). The aorta was cut into a 2 mm long ring, transferred to an organ bath filled with 5 mL of Krebs-Henseleit buffer, and connected to a myograph (DMT, Denmark). The buffer solution was heated to 37 ° C., and 95% oxygen and 5% carbon dioxide were blown. To measure isometric muscle contraction, an aortic ring was attached between the two hooks. One hook was connected to the pressure transducer. The second hook was mobile and the correct initial load setting was made according to the protocol reported by Mulvany and Halpern (Circulation Research 1977; 41: 19-26).

  Before each experiment, the responsiveness of the specimen was examined by adding potassium-containing Krebs-Henseleit solution (50 mmol / L KCl). The synthetic peptide, angiotensin 1-18, was used to induce contraction of the aortic ring. Angiotensin 1-18 is converted to angiotensin II independently of ACE. The aortic ring was then incubated with the test substance for 20 minutes and the contraction measurement was repeated. Chymase inhibition is shown as a decrease in contraction induced by angiotensin 1-18.

B-3. Male Syrian hamsters weighing 130-160 g were used for isoprenaline-induced cardiac fibrosis model experiments in hamsters. Cardiac hypertrophy and cardiac fibrosis were induced by subcutaneous injection of 20 mg / kg isoprenaline once a day for 7 days. Animals were orally administered test substances 2 hours prior to isoprenaline injection. In the control group, the solvent was administered subcutaneously and orally in a corresponding manner. At the end of the experiment, the heart was removed, weighed and fixed. Fibrous tissue on the surface of tissue sections from the heart was marked using Sirius Red staining. Next, the fibrous area was determined by area measurement.

C. Working Examples of Pharmaceutical Compositions The compounds of the present invention can be converted into pharmaceutical formulations as follows.

tablet
Composition 100 mg of the compound of the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (natural), 10 mg of polyvinylpyrrolidone (PVP25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

  Tablet weight 212mg, diameter 8mm, curvature radius 12mm.

Production A mixture of a compound of the invention, lactose and starch is granulated using a 5% solution (m / m) aqueous PVP solution. After drying, the granules are mixed with magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (see above for tablet form). The guide value used for tableting is a pressure of 15 kN.

Suspension for oral administration
Composition 1000 mg of the compound of the invention, 1000 mg ethanol (96%), 400 mg Rhodigel® (xanthan gum from FMC (Pennsylvania, USA)) and 99 water.

  One dose of 100 mg of the compound of the invention corresponds to 10 mL of oral suspension.

The produced Rhodigel is suspended in ethanol and the compound of the invention is added to the suspension. Add water with stirring. Stir the mixture for about 6 hours until Rhodigel stops swelling.

Solution for oral administration
Composition 500 mg of the compound of the invention, 2.5 g polysorbate and 97 g polyethylene glycol 400. One dose of 100 mg of the compound of the present invention corresponds to 20 g of oral solution.

The compound of the present invention is suspended in a mixture of manufactured polyethylene glycol and polysorbate with stirring. Stirring is continued until dissolution of the compound of the invention is complete.

Intravenous Solution The compound of the present invention is dissolved in a physiologically acceptable solvent (eg, isotonic sodium chloride solution, glucose solution 5% and / or PEG 400 solution 30%) at a concentration below the saturation solubility. The resulting solution is sterile filtered and dispensed into sterile, pyrogen-free injection containers.

Claims (11)

Compounds of formula (I) and salts, solvates and solvates of the compounds.

[Where:
R ¹ is hydrogen or (C ₁ -C ₄ ) -alkyl;
R ² is a group of the following formula:

And
Where
^* Is the bonding site to the uracil nitrogen atom,
A is _{-CH 2 -, - CH 2 -CH} 2 -, - O-CH 2 - is ## or oxygen,
## is the bonding point to the phenyl ring,
m is the number 0, 1 or 2;
R ⁴ is halogen, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, difluoromethoxy, trifluoromethoxy or (C ₁ -C ₄ ) -alkoxy;
R ^5A is hydrogen or deuterium;
R ^5B is hydrogen, deuterium or (C ₁ -C ₄ ) -alkyl;
R ⁶ is hydrogen or fluorine;
R ⁷ is hydrogen or fluorine,
R ⁸ is halogen, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl or nitro;
R ⁹ is hydrogen, halogen, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, nitro or (C ₁ -C ₄ ) -alkylthio;
R ³ is a group of the following formula:

And
Where
# Is the point of attachment to the uracil nitrogen atom,
Ring Q is a 5- to 7-membered heterocycle or 5- or 6-membered heteroaryl, wherein
5- to 7-membered heterocycle and 5- or 6-membered heteroaryl are halogen, difluoromethyl, trifluoromethyl, trideuterated methyl, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) — Independently selected from the group of cycloalkyl, oxo, hydroxyl, (C ₁ -C ₄ ) -alkylcarbonyl, (C ₁ -C ₄ ) -alkoxycarbonyl, aminocarbonyl and (C ₁ -C ₄ ) -alkylsulfonyl Optionally substituted by 1 to 4 substituents,
(C ₁ -C ₆ ) -alkyl and (C ₃ -C ₇ ) -cycloalkyl are then halogen, cyano, trifluoromethyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl, (C ₁ -C ₄ ) -Alkoxy and optionally substituted by 1 to 3 substituents independently selected from the group of 4 to 7 membered heterocycles;
Two (C ₁ -C ₆ ) -alkyl groups attached to a 5- to 7-membered heterocycle and a 5- or 6-membered heteroaryl carbon atom together with the carbon atom to which they are attached It may form a 6-membered carbocycle,
R ²⁴ is halogen, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -alkoxy,
n is the number 0, 1, 2, or 3. ] R ¹ is hydrogen, methyl or ethyl;
R ² is a group of the following formula:

And
Where
^* Is the bonding site to the uracil nitrogen atom,
A _{is, -CH 2 -, - CH 2} -CH 2 -, - O-CH 2 - is ## or oxygen,
## is the bonding site to the phenyl ring,
R ^4A is hydrogen, fluorine, chlorine, trifluoromethyl or methyl;
R ^4B is hydrogen, fluorine, chlorine, trifluoromethyl or methyl;
Provided that at least one of the R ^4A and R ^4B groups is other than hydrogen;
R ^5A is hydrogen;
R ^5B is hydrogen;
R ⁶ is hydrogen;
R ⁷ is hydrogen;
R ⁸ is fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl;
R ⁹ is fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl;
R ³ is a group of the following formula:

And
Where
# Is the bonding site to the uracil nitrogen atom,
E ¹ is CR ¹¹ or N;
R ¹¹ is hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or aminocarbonyl;
E ² is CR ¹² or N;
R ¹² is hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl;
E ³ is NR ¹⁴ or S;
R ¹⁴ is hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl;
G ¹ is C═O or SO ₂ ,
G ² is CR ^16A R ^16B , NR ¹⁷ , O or S;
R ^16A is hydrogen, fluorine, (C ₁ -C ₄ ) -alkyl or hydroxyl;
R ^16B is hydrogen, fluorine, chlorine, (C ₁ -C ₄ ) -alkyl or trifluoromethyl;
Or R ^16A and R ^16B together with the carbon atom to which they are attached form a 3- to 6-membered carbocycle;
R ¹⁷ is hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or (C ₁ -C ₄ ) -alkoxycarbonyl;
(C ₁ -C ₆ ) -alkyl is fluorine, trifluoromethyl, cyano, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, azetidinyl, oxetanyl, Optionally substituted by 1 to 3 substituents independently selected from the group of tetrahydrofuranyl and pyrrolidinyl,
G ³ is CR ^18A R ^18B , NR ¹⁹ , O or S;
R ^18A is hydrogen, fluorine, (C ₁ -C ₄ ) -alkyl or hydroxyl;
R ^18B is hydrogen, fluorine, chlorine, (C ₁ -C ₄ ) -alkyl or trifluoromethyl;
Or R ^18A and R ^18B together with the carbon atom to which they are attached form a 3 to 6 membered carbocycle;
R ¹⁹ is hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or (C ₁ -C ₄ ) -alkoxycarbonyl;
(C ₁ -C ₆ ) -alkyl is fluorine, trifluoromethyl, cyano, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, azetidinyl, oxetanyl, Optionally substituted by 1 to 3 substituents independently selected from the group of tetrahydrofuranyl and pyrrolidinyl,
G ⁴ is CH ₂ , C═O or SO ₂ ,
K ¹ is CH ₂ or O;
K ² is CH ₂ or O;
Provided that only one of the K ¹ and K ² groups is O;
D ¹ , D ² , D ³ and D ⁴ are each independently CR ²³ or N;
R ²³ is hydrogen, halogen, (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,
Provided that no more than ^{two of} the D ¹ , D ² , D ³ and D ⁴ groups are N;
R ²⁴ is fluorine or methyl;
n is the number 0 or 1;
R ¹⁰ is (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl;
₁ or _{2 wherein} (C ₁ -C ₄ ) -alkyl is independently selected from the group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl May be substituted by a substituent,
R ¹³ is hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl;
R ¹⁵ is hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl;
₁ or 2 wherein (C ₁ -C ₆ ) -alkyl is independently selected from the group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl May be substituted by a substituent,
R ²⁰ is hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or (C ₁ -C ₄ ) -alkylcarbonyl;
₁ or 2 wherein (C ₁ -C ₆ ) -alkyl is independently selected from the group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl May be substituted by a substituent,
R ²¹ is hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or (C ₁ -C ₄ ) -alkylsulfonyl;
R ^22A is hydrogen or (C ₁ -C ₄ ) -alkyl;
R ^22B is hydrogen or (C ₁ -C ₄ ) -alkyl;
Or R ^22A and R ^22B together with the carbon atom to which they are attached form a carbonyl group and the compound of formula (I) according to claim 1 and salts, solvates and solvates of the compounds of the compound . R ¹ is hydrogen;
R ² is a group of the following formula:

And
Where
^* Is the bonding site to the uracil nitrogen atom,
A is —CH ₂ —;
R ^4A is chlorine or trifluoromethyl;
R ^4B is hydrogen;
R ³ is a group of the following formula:

And
Where
# Is the bonding site to the uracil nitrogen atom,
E ¹ is CR ¹¹
R ¹¹ is hydrogen;
E ² is N;
G ¹ is C = O,
G ² is CR ^16A R ^16B , NR ¹⁷ , O or S;
R ^16A is hydrogen, fluorine, methyl or hydroxyl;
R ^16B is hydrogen, fluorine, methyl or trifluoromethyl;
Or R ^16A and R ^16B together with the carbon atom to which they are attached form a cyclopropyl ring;
R ¹⁷ is hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₅ ) -cycloalkyl;
(C ₁ -C ₄ ) -alkyl is independently selected from the group of fluorine, trifluoromethyl, cyano, cyclopropyl, cyclobutyl, hydroxyl, trifluoromethoxy, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl. Optionally substituted by 1 to 3 substituents,
R ²⁴ is hydrogen or fluorine,
R ¹⁰ is (C ₁ -C ₄ ) -alkyl;
R ¹⁵ is hydrogen, methyl or ethyl;
3. A compound of formula (I) as defined in claim 1 or 2 and a salt of said compound, wherein methyl and ethyl may be substituted by one substituent selected from the group of fluorine, trifluoromethyl and cyclopropyl , Solvates and solvates of salts. R ¹ is hydrogen;
R ² is a group of the following formula:

And
Where
^* Is the bonding site to the uracil nitrogen atom,
R ^5A is hydrogen;
R ^5B is hydrogen;
R ⁶ is hydrogen;
R ⁷ is hydrogen;
R ⁸ is fluorine, chlorine or trifluoromethyl;
R ⁹ is fluorine, chlorine, trifluoromethyl or methyl;
R ³ is a group of the following formula:

And
Where
# Is the bonding site to the uracil nitrogen atom,
E ¹ is CR ¹¹ and R ¹¹ is hydrogen;
E ² is N;
G ¹ is C = O,
G ² is CR ^16A R ^16B , NR ¹⁷ , O or S;
R ^16A is hydrogen, fluorine, methyl or hydroxyl;
R ^16B is hydrogen, fluorine, methyl or trifluoromethyl;
Or R ^16A and R ^16B together with the carbon atom to which they are attached form a cyclopropyl ring;
R ¹⁷ is hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₅ ) -cycloalkyl;
(C ₁ -C ₄ ) -alkyl is independently selected from the group of fluorine, trifluoromethyl, cyano, cyclopropyl, cyclobutyl, hydroxyl, trifluoromethoxy, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl. Optionally substituted by 1 to 3 substituents,
R ²⁴ is hydrogen or fluorine,
R ¹⁰ is (C ₁ -C ₄ ) -alkyl;
R ¹⁵ is hydrogen, methyl or ethyl;
3. A compound of formula (I) as defined in claim 1 or 2 and a salt of said compound, wherein methyl and ethyl may be substituted by one substituent selected from the group of fluorine, trifluoromethyl and cyclopropyl , Solvates and solvates of salts. [A] Compound of the following formula (II):

(Where
R ^1A is (C ₁ -C ₄ ) -alkyl;
T ¹ is (C ₁ -C ₄ ) -alkyl;
T ² is (C ₁ -C ₄ ) -alkyl. ) In an inert solvent, optionally in the presence of a suitable base:

(Wherein R ³ is as defined in claims 1 to 4) and a compound of the following formula (IV):

(Wherein R ^1A and R ³ are each as defined above)
This is then carried out in the presence of a suitable base in an inert solvent in the following formula (V):

(Where
R ² is as defined in claims 1 to 4;
X ¹ is hydroxyl or a suitable leaving group, in particular chlorine, bromine or iodine. And a compound of the following formula (I-1):

In which R ^1A , R ² and R ³ are each as defined above.
Or [B] a compound of formula (VI):

(Where
R ^1A and T ¹ are each as defined above,
T ³ is (C ₁ -C ₄ ) -alkyl. ) With a compound of formula (III) in an inert solvent or without solvent, a compound of formula (VII)

(Wherein R ^1A , R ³ and T ³ are each as defined above),
This is then reacted with chlorosulfonyl isocyanate in an inert solvent to give a compound of formula (IV), which is then converted to a compound of formula (I-1) in a manner similar to method [A]. ,
Or [C] a compound of the following formula (VIII):

(Wherein R ² is as defined in claims 1 to 4) in an inert solvent, a compound of formula (IX):

(Where
R ^1A and T ¹ are each as defined above, and T ⁵ is (C ₁ -C ₄ ) -alkyl. )
Cyclization in the presence of a suitable base gives a compound of formula (X)

(Wherein R ^1A and R ² are each as defined above) and are then obtained in the presence of a suitable catalyst and a suitable base in an inert solvent in the following formula (XI ) Compound:

(Where
R ³ is as defined above,
T ⁶ is hydrogen, (C ₁ -C ₄ ) -alkyl, or the two T ⁶ groups together form a —C (CH ₃ ) ₂ —C (CH ₃ ) ₂ — bridge. To obtain a compound of formula (I-1),
Or [D] hydrolyzing the compound of formula (I-1) in the presence of a suitable acid or base in an inert solvent to give a compound of formula (I-2):

(Where
R ² and R ³ are each as defined in claims 1 to 4;
R ^1B is hydrogen. )
The protecting group is removed and / or, where appropriate, and / or the compounds of formulas (I-1) and (I-2) are used with a suitable (i) solvent and / or (ii) a base or acid. A process for the preparation of a compound of formula (I), which is converted to a solvate, salt and / or solvate of the salt   5. A compound as defined in any one of claims 1 to 4 for the treatment and / or prevention of a disease.   5. Use in a method for the treatment and / or prevention of heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, renal failure, nephropathy, visceral fibrosis and dermal fibrosis. A compound as defined in   5. A medicament comprising a compound as defined in any one of claims 1 to 4 in combination with one or more inert and non-toxic medicament suitable excipients.   Calcium antagonist, angiotensin AII antagonist, ACE inhibitor, vasopeptidase inhibitor, endothelin antagonist, renin inhibitor, α-receptor blocker, β-receptor blocker, mineralocorticoid receptor antagonist, rho kinase inhibitor Claim 1 in combination with one or more further active ingredients selected from the group consisting of drugs, diuretics, kinase inhibitors, matrix metalloprotease inhibitors, stimulators and activators of soluble guanylate cyclase, and phosphodiesterase inhibitors A medicament comprising the compound as defined in any one of 1 to 4.   The medicament according to claim 7 or 8, for the treatment and / or prevention of heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, renal failure, nephropathy, visceral fibrosis and skin fibrosis.   Heart failure, lungs in humans and animals, using an effective amount of at least one compound as defined in any one of claims 1 to 4 or a medicament as defined in any one of claims 7 to 9. A method for the treatment and / or prevention of hypertension, chronic obstructive pulmonary disease, asthma, renal failure, nephropathy, visceral fibrosis and skin fibrosis.